
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION


MEMORANDUM


Date:  		November 25, 2013

SUBJECT:	Indoxacarb. Human Health Risk Assessment for the Proposed New Use on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13-07F and Low Growing Berry Subgroup (except strawberry) 13-07H. 

 
PC Code:  067710 
DP Barcode: D416367 
Decision No.: 464583
Registration No.:  352-579 and 352-638
Petition No.: 2E8029 
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical Aggregate   
Case No.:  NA
TXR No.:  NA
CAS No.:  173584-44-6
MRID No.:  NA
40 CFR: §180.564


FROM:		Danette Drew, Chemist
		Ideliz Negrón-Encarnación, Ph.D., Chemist
		Ana Rivera-Lupiáñez, Chemist 
		William Irwin, Ph.D., Toxicologist
	   	Risk Assessment Branch V/VII
		Health Effects Division (7509P)


THROUGH:	Michael Metzger, Branch Chief
		Risk Assessment Branch V/VII
		Health Effects Division (7509P)
		

TO:		Laura Nollen, Risk Manager
		Barbara Madden, Risk Manager
		Risk Integration, Minor Use & Emergency Response Branch
		Registration Division (7505P)





1.0	Executive Summary	4
2.0	HED Recommendations	7
2.1	Data Deficiencies	7
2.2	Tolerance Considerations	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	8
2.2.3	Revisions to Petitioned-For Tolerances	9
2.2.4	International Harmonization	9
2.3	Label Recommendations	10
2.3.1	Recommendations from Residue Reviews	10
2.3.2	Recommendations from Occupational Assessment	10
2.3.3	Recommendations from Residential Assessment	10
3.0	Introduction	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	11
3.3	Pesticide Use Pattern	12
3.4	Anticipated Exposure Pathways	13
3.5       Consideration of Environmental Justice	13
4.0	Hazard Characterization and Dose-Response Assessment	14
4.1	Summary of Toxicological Effects	14
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)	16
4.2.1	Completeness of the Toxicology Database	16
4.2.2	Evidence of Neurotoxicity	16
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	17
4.2.4	Residual Uncertainty in the Exposure Database	17
4.3	Toxicity Endpoint and Point of Departure Selections	17
5.0	Dietary Exposure and Risk Assessment	21
5.1	Residues of Concern Summary and Rationale	21
5.2	Food Residue Profile	22
5.3	Water Residue Profile	23
5.4	Dietary Risk Assessment	24
5.4.1	Description of Residue Data Used in Dietary Assessment	24
5.4.2	Percent Crop Treated Used in Dietary Assessment	24
5.4.3    Acute Dietary Risk Assessment	25
5.4.4	Chronic Dietary Risk Assessment	25
5.4.5	Summary Table	25
6.0     Residential (Non-Occupational) Exposure/Risk Characterization	26
6.1	Residential Handler Exposure	26
6.2	Residential Post-Application Exposure	29
6.3	Residential Risk Estimates for Use in Aggregate Assessment	34
6.4	Residential Bystander Post-application Inhalation Exposure	37
6.5	Spray Drift	37
7.0      Aggregate Exposure/Risk Characterization	38
7.1	Acute Aggregate Risk	38
7.2     Short- and Intermediate-Term Aggregate Risk	38
7.3	Long-Term (Chronic) Aggregate Risk	39
7.4	Cancer Aggregate Risk	40
8.0    Cumulative Exposure/Risk Characterization	40
9.0    Occupational Exposure/Risk Characterization	40
9.1	Short- and Intermediate- Term Handler Risk	42
9.2	Short- and Intermediate-Term Post-Application Risk	45
9.2.1	Dermal Post-Application Risk	46
9.2.2	Inhalation Post-Application Risk	46
10.0	References	47
Appendix A.  Toxicology Profile and Executive Summaries	48
Appendix B.  Physical/Chemical Properties	55
Appendix C.  Review of Human Research	56


1.0	Executive Summary

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment to support an IR-4 petition (PP#2E8029) for the proposed foliar uses of the insecticide indoxacarb on the following agricultural crops: 1) new uses on dry beans and succulent beans and 2) expanded crop group uses on small fruit vine climbing subgroup 13-07F (except kiwifruit) and low-growing berry subgroup 13-07H (except strawberry). 

Indoxacarb, (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl] amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate, is an oxadiazine class insecticide active ingredient (ai).  It is registered for use in both agricultural and residential sites.  Permanent tolerances are established under 40 CFR 180.564(a) for the combined residues of indoxacarb and its R-enantiomer on a number of plant as well as livestock commodities (tolerances on poultry commodities also include several indoxacarb metabolites).  The primary residues of toxicological concern for risk assessment are indoxacarb (S-enantiomer) and its R-enantiomer; various metabolites and degradates are also included as residues of concern in milk, poultry commodities and drinking water.  This assessment takes into account the proposed crop uses and previously registered uses on other crops and in residential sites.

Indoxacarb is formulated as granular; impregnated materials; water dispersible granules; emulsifiable, flowable and soluble concentrates; and solution-ready-to-use products.  Indoxacarb products are frequently formulated as a mixture of the insecticidally active S-enantiomer and the insecticidally inactive R-enantiomer.  The percent active ingredient and application rates listed on indoxacarb product labels only reflect the S-enantiomer; labels do not reflect the amount of R-enantiomer in the mixtures.  Adjustments are made in this assessment to add in the percent of R-enantiomer in product mixtures so that the total amount of indoxacarb applied (both S- and R- enantiomers) is considered.  The term `indoxacarb' generally refers to the S-enantiomer (also called DPX-KN128 or KN128) but may also refer to a mixture.  Mixtures may appear as 1) isomer enriched DPX-MP062 (also referred to as MP062) which is a mixture containing the S-enantiomer and its R-enantiomer at approximately a 75:25 ratio, or 2) racemic mixture DPX-JW062 (also referred to as JW062) which is a mixture of the enantiomers at a 50:50 ratio.  The R-enantiomer is also referred to as IN-KN127 or KN127. 

The database for indoxacarb is complete and is sufficient for characterizing toxicity.  Toxicology studies have been performed using either MP062 or JW062 (S-enantiomer and R-enantiomer mixtures) or the KN128 (S-enantiomer only). 

The toxicity profiles for KN128, MP062 and JW062 in rats, mice and dogs with both subchronic and chronic oral exposures were qualitatively similar.  The endpoints that most frequently defined the lowest-observed-adverse-effect-level (LOAEL) were non-specific, and included decreases in body weight, weight gain, food consumption and food efficiency.  These compounds also affected the hematopoietic system by decreasing the red blood cell count, hemoglobin and hematocrit in rats, dogs and mice.  

There was no evidence of reproductive effects in the 2-generation reproduction study in rats. There was no evidence of susceptibility from either in utero or neonatal exposure to both rat and rabbit young or in the developmental neurotoxicity study in rats.  Neurotoxicity was seen in animal studies in rats and mice but at doses much higher than those selected for points of departure (which are based on changes in body weight, food consumption and changes in hematology) for the current risk assessment.  There is no evidence of teratogenicity, mutagenicity, or carcinogenicity in the indoxacarb studies.

The FQPA safety factor (SF) for indoxacarb is reduced to 1X based on the following:  1) the hazard and exposure databases are complete; 2) there are no concerns for pre- and/or postnatal toxicity; 3) there are no residual uncertainties with regard to pre- and/or post-natal toxicity; and 4) the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) and developmental neurotoxicity (DNT) studies are available and all endpoints used in this risk assessment are protective of any neurotoxic effects.

The only new toxicity information received since the last indoxacarb risk assessments (D351087, 5/18/09, Indoxacarb. Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13-07B and Beets (Garden) and D365306, 5/26/09, Indoxacarb.  Addendum to the Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13-07B and Beets (Garden)) is the immunotoxicity study, which did not indicate immunotoxic potential for indoxacarb.  The toxicity endpoints have not changed with the exception of the addition of a long-term oral endpoint to cover residential uses of that duration and a revision to the dermal toxicity endpoint.  The long-term oral endpoint and point of departure are the same as those selected for short- and intermediate  - term durations.  A re-evaluation of the available dermal toxicity studies, including rat in vivo, and rat and human in vitro studies, has been performed.  Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity is therefore not expected in humans.

Acute and chronic dietary (combined food and drinking water) assessments were performed for indoxacarb using partially refined assumptions such as residues from field trail data and, where available, percent crop treated estimates and processing factors.  Estimated drinking water concentrations were derived from modeling procedures. The resulting acute and chronic dietary exposures are below HED's level of concern for the general U.S. population and all population subgroups (aPAD or cPAD <100%).  

No new residential uses are being requested with this petition; however, there are existing residential uses (ornamental lawns and turf/golf courses, and spot-on applications for the control of fleas and ticks on domestic animals) that have been previously assessed and are assessed herein to reflect updates to HED's 2012 Residential SOPs, policy changes for body weight assumptions, and a re-evaluation of the dermal toxicity of indoxacarb.  In addition, there are existing residential uses (insect control treatments of household premises; Arilon Insecticide 20% ai, EPA Reg. No. 100-1501 and  Aperion Insecticide 14.5% ai ,EPA Reg. No. 352-770) which do not appear to have been previously assessed and are assessed herein. 

Indoxacarb RTU bait stations and gels products are formulated at very low application rates and are designed to be self-contained; therefore, handler contact is expected to be negligible and post-application exposures are not expected.  Exposure and risk for these uses were not quantified.  Inhalation assessments are not performed for applying pet spot-on treatments as inhalation exposure is not expected from these uses. Dermal exposures are expected to be negligible when applying spot-on products; in addition, indoxacarb does not have a dermal toxicity endpoint for humans. Therefore, a quantitative handler assessment is not performed for the indoxacarb pet spot-on treatments.

Residential adult handler scenarios assessed include turf applications and indoor spray applications (inhalation only).  Residential post-application scenarios assessed include 1) children's exposure (inhalation and non-dietary oral) to treated pets, treated turf and spray-treated indoor surfaces and 2) adult exposure to spray-treated indoor surfaces (inhalation only). 

Most indoxacarb residential handler (adult) and post-application (adult and children) exposure scenarios result in risk estimates below HED's level of concern.  However, for spot-directed treatments of the indoor directed spray, incidental oral (hand-to-mouth) exposure estimates alone for children exceed HED's level of concern.  For crack and crevice treatment only scenario of the indoor directed spray, the combined inhalation and incidental oral risk estimates for children are not of concern.  

Based on the existing and newly proposed uses of indoxacarb, exposures can occur both from dietary sources (food and water) and in residential settings.  Acute, short-term, intermediate-term and long-term (chronic) aggregate (combined food, water and residential exposure) assessments were performed for indoxacarb.  The scenarios resulting in the highest exposures are selected as protective scenarios for the aggregate assessments.  There are no acute, short-term, intermediate-term, or long-term (chronic) aggregate risk estimates of concern for adult (handler or post-application) or child (post-application) exposure to indoxacarb as a result of current and proposed uses.  Note: the aggregate assessment for indoor surface directed spray assumed only crack and crevice treatment.  The residential post-application (hand-to-mouth) exposure to the spot-directed sprays resulted in risks of concern for children and was not used in the aggregate assessment.  At this time, labels for the indoor surface directed sprays do not limit the use to only crack and crevice.

A quantitative dermal risk assessment is not required for indoxacarb.  All occupational handler scenarios assessed associated with the proposed uses result in inhalation MOEs that do not exceed HED's level of concern (MOEs >= 100) for short- and intermediate-term exposure durations at label specified personal protective equipment (PPE).  Further, there were no risks of concern identified for post-application exposure to indoxacarb associated with these new uses. No additional (PPE) is required.  The label restricted entry interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard requirements.  

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898 (see Section 3.5 of this document).  For information regarding human studies, see Appendix C.
2.0	HED Recommendations

Assuming spot-directed spray treatments are removed from residential product labels (i.e. use limited to crack and crevice only), HED has no objection to  registration and associated tolerances for the use of indoxacarb on dry beans, succulent beans, small fruit vine climbing subgroup 13-07F (except kiwifruit) and low growing berry subgroup 13-07H (except strawberry).  Additional requirements are outlined in Section 2.1 below.  The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1	Data Deficiencies

Residue Chemistry

860.1200 Directions for Use

The proposed label directions are adequate for evaluating the residue data for the proposed new uses.  However, the labels should be revised to clarify discrepancies or add specificity (see Section 2.3.1 of this document).

860.1550 Proposed Tolerances

A revised Section F should be submitted according to Table 2.2.2. 

860.1650 Submittal of Analytical Reference Standards 

An analytical standard for the insecticide indoxacarb is currently available in the EPA National Pesticide Standards Repository.  However, the indoxacarb standard has an expiration date of 4/2013.  A reference standard should be sent to the Analytical Chemistry Laboratory located in Fort Meade to the attention of either Theresa Cole or Thuy Nguyen at the following address:

      USEPA
      National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
      701 Mapes Road
      Fort George G. Meade, MD  20755-5350

Please note that mail will be returned if the entire extended zip code is not used when addressing correspondence to the Repository. 

Toxicology and Hazard
None.

Occupational and Residential Exposure
None.
2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

A number of adequate methods are available for enforcing indoxacarb tolerances on plant commodities.  These protocols are all common moiety methods which measure both indoxacarb and its R-enantiomer as a single component. 

The primary protocol for the tolerance enforcement of plant commodities is DuPont method AMR 2712-93 which is an HPLC/UV procedure.  It has been validated by the Agency and forwarded to the FDA for inclusion in PAM Vol. II (D267339, S. J. Levy, 10/12/2000).  

For the confirmation of residues in plant commodities, DuPont method AMR 3493-95 Supplement No. 4 is a GC/MSD procedure is also available.  This method has also been validated by the Agency and forwarded to the FDA accordingly (D282821, S. J. Levy, 05/09/2002).   Residues are quantified using the m/z 527 ion, and confirmatory analyses utilize the 218, 321 and 527 ions.  
    
Another HPLC/UV procedure developed by the registrant, DuPont-11978, is also available for tolerance enforcement analyses (D313518, S. J. Levy, 02/18/2005).  This protocol works by uniquely combining the extraction procedure of method AMR-3493-95 with the cleanup and determination techniques developed in method AMR 2712-93.  

2.2.2	Recommended Tolerances

HED recommends that 40 CFR 180.564 be amended by establishing or removing tolerances for the plant commodities as listed in the Table 2.2.2.  Tolerances for livestock commodities and rotational crops are not needed to support the proposed uses of indoxacarb.  The tolerances for indoxacarb in plant commodities are defined as follows: Tolerances are established for residues of indoxacarb, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only indoxacarb, (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2- e ][1,3,4][oxadiazine-4a(3 H )-carboxylate, and its R-enantiomer, (R)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2- e ][1,3,4][oxadiazine-4a(3 H )-carboxylate, in or on the commodity.








Table 2.2.2.  Tolerance Summary for Indoxacarb.
Commodity
                     Established/Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                    Comments (correct commodity definition)
Bean, dry, seed
                                     0.07
                                      0.2

Pea, southern, seed
                                      0.1
                                    Remove

Bean, succulent
                                     0.64
                                      0.9

Bean, forage
                                      37
                                      50
Cowpea, forage
Cowpea, hay
                                      --
                                      100

Small fruit vine climbing, except fuzzy kiwifruit, subgroup 13-07F
                                      2.0
                                       2

Low growing berry, except strawberry, subgroup 13-07H
                                      0.9
                                       1

Cranberry
                                     0.90
                                    Remove

Grape
                                      2.0
                                    Remove



2.2.3	Revisions to Petitioned-For Tolerances

The registrant-proposed tolerances for indoxacarb are different from those recommended by the HED.  The recommended tolerances were derived by using the Organization for the Economical Cooperation and Development (OECD) calculation procedures while the registrant used the North America Free Trade Agreement (NAFTA) calculation procedures.  In addition, the tolerance for indoxacarb on dry beans covers the southern pea variety (cowpea) which already has a tolerance established in the CFR.  Since the forage and hay of cowpea are the only significant feedstuff associated with dry beans, the correct commodity definition would be cowpea, forage instead of bean, forage.  HED is recommending a tolerance be established for residues of indoxacarb on cowpea hay; a tolerance for cowpea hay was not proposed. In order to harmonize with the Codex maximum residue level (MRL) for cowpea (see discussion in 2.2.4 below), the tolerance for dry bean obtained by the OECD calculation procedures (0.06 ppm) will be increased to 0.2 ppm.  The registrant should submit a revised Section F in which the proposed tolerances are the same as those recommended by the HED.

2.2.4	International Harmonization

U.S. tolerances are recommended for dry beans, succulent beans, small fruit vine climbing subgroup 13-07F, and low growing berry subgroup 13-07H based on residues of indoxacarb and its R-enantiomer.  Maximum residue limits (MRLs) have not been established by Canada or Mexico.  However, Codex has established MRLs for grapes (2 ppm), dry grapes (5.0 ppm), cranberries (1ppm), dry chick-pea (0.2 ppm), dry mung bean (0.2 ppm), and dry cowpea (0.1 ppm) based on measurement of indoxacarb and its R-enantiomer.  The U.S. tolerances for raisins (5.0 ppm) and cranberries (1 ppm) are harmonized with the corresponding Codex MRLs.  The U.S. tolerance for grapes (subgroup 13-07F) obtained with the OECD calculator (3 ppm) is higher than the Codex MRL for grapes (2 ppm).  The U.S. crop field trial data for grapes show that the highest residue is 1.74 ppm, and the registrant proposed a tolerance level of 2.0 ppm.  HED recommends establishment of a grape tolerance level of 2 ppm in order to harmonize with Codex.  The tolerance level for dry bean (0.06 ppm) obtained by the OECD calculation procedures will be increased to 0.2 ppm in order to harmonize with the Codex MRLs for dry chick pea and dry mung bean. 

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

The following label recommendations are needed to clarify discrepancies or add specificity:
 
   * Under the application instructions (page 3 of Avaunt[(R)] label) include dry bean in the sentence "For bushberry, cranberry, dry bean, pome and stone fruit the minimum interval between treatments is 7 days." 

   * Under the tabulated instructions (page 6 of Avaunt[(R)] label and page 5 of Steward[(R)] EC label) for dry bean and/or succulent bean edit the sentence "Make a uniform application in approximately 20-100 gallons of water per acre" to specify the volume for ground and/or aerial applications.

2.3.2	Recommendations from Occupational Assessment

None.

2.3.3	Recommendations from Residential Assessment

The assessment for indoxacarb indoor surfaces directed sprays resulted in post-application risk estimates of concern for children for spot-directed treatment scenarios; however, when the surfaces directed spray treatments were assumed to be limited to crack and crevice only, risk estimates were not of concern.  HED recommends amending the EPA Reg. No. 100-1501 label to restrict indoor residential uses to only crack and crevice treatments limiting applications to areas not accessible to young children; any spot, perimeter, or baseboard treatments should be restricted on the label.
3.0	Introduction

3.1	Chemical Identity







Table 3.1	Indoxacarb Nomenclature.
Compound
                                       
Common name
Indoxacarb
Company experimental name
DPX-KN128
IUPAC name
(S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate
CAS name
methyl (4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-
(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate
CAS registry number
173584-44-6
End-use product (EP)
30% WDG (DuPont Avaunt[(R)] Insecticide; EPA Reg. No. 352-597) and 16% Emusifiable Concentrate (Steward[(R)] EC Insecticide; EPA Reg. No. 352-638)
Compound
                                       
Common name
R-enantiomer of indoxacarb
Company name
IN-KN127 (pesticidally inactive)

3.2	Physical/Chemical Characteristics

Indoxacarb has a very low vapor pressure of 1.9x10[-10] mm Hg at 25 ºC; volatilization is not expected to be a significant route of dissipation for this pesticide.  The octanol water partition coefficient (Kow = 44000) suggests that it is lipophilic.  Indoxacarb is slightly soluble in water (0.8 mg/L at pH 7). 

Indoxacarb is stable to aqueous photolysis and hydrolysis.  Aerobic aquatic, aerobic soil, and anaerobic aquatic metabolism of indoxacarb results in half-lives of 71 days, 267 days, and 577 days, respectively.
SEE APPENDIX B FOR A TABLE OF Physicochemical properties of indoxacarb.

3.3	Pesticide Use Pattern

IR-4 has submitted field trial data in support of a petition proposing tolerances for the use of Avaunt(R) WDG and Steward[(R)] EC on dried beans and Avaunt[(R)] WDG on succulent beans.  In addition, crop subgroup tolerances and registration of Avaunt[(R)] WDG for use on small fruit vine climbing subgroup (except kiwifruit) 13-07F, and low growing berry subgroup (except strawberry) 13-07H are proposed based on established tolerances for grapes and cranberries.  The proposed new uses are summarized below in Table 3.3. Refer to section 2.3 for recommended modifications to the proposed labels.

Table 3.3	Summary of Directions for Use of Indoxacarb.
Applic. Timing, Type, and Equip. [1]
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                              Use Directions and 
                                Limitations [2]
                                Bean, succulent
Broadcast foliar applications when insects reach economic thresholds; ground or air equipment
                                    30% WDG
                                   [352-597]
                                     0.11
                                      NS
                                     0.44
                                       3
A minimum 7-day RTI is specified.  Make a uniform application of approximately 20-100 gal/A.
                                   Bean, dry
Broadcast foliar applications when insects reach economic thresholds; ground or air equipment
                                    30% WDG
                                   [352-597]
                                     and 
                                    16% EC
                                   [352-638]
                                     0.11
                                      NS
                                     0.44
                                       7
A minimum 7-day RTI is specified.  Make a uniform application of approximately 20-100 gal/A.
      Small fruit vine climbing, except fuzzy kiwifruit, subgroup 13-07F
Broadcast foliar applications when insects reach economic thresholds; ground or air equipment
                                    30% WDG
                                   [352-597]
                                     0.11
                                      NS
                                     0.22
                                       7
A minimum 21-day RTI is specified.  Apply in a minimum of 10 gal/A and 50 gal/A for aerial and ground applications, respectively.
             Low growing berry, except strawberry, subgroup 13-07H
Broadcast foliar applications when insects reach economic thresholds; ground or air equipment
                                    30% WDG
                                   [352-597]
                                     0.11
                                      NS
                                     0.44
                                      30
A minimum 7-day RTI is specified.  Apply in a minimum of 5 gal/A and 10 gal/A for aerial and ground applications, respectively.
[1]	Do not apply through any type of irrigation system, expect for application to cranberry, mint, potato, and sweet corn, and as allowed on supplemental labels.
[2]	Applications may include the use of an adjuvant.  Rotational crop restrictions: (1) 30%WDG: Crops with labeled uses and alfalfa, cotton, peanuts and soybeans may be planted immediately following harvest of a treated crop.  Do not plant any food or feed crops not registered for use with indoxacarb for 30 days after last use. (2) 16% EC:  Crops that are on this label and all brassica leafy vegetables, cucurbit vegetables, fruiting vegetables, leafy green vegetables, leafy petiole vegetables, pome fruit and stone fruit, plus sweet corn, cranberry, grape, mint, southern pea and the tuberous and corm vegetables found in crop subgroup 1C (arracacha, arrowroot, Chinese artichoke, edible canna (Queensland arrowroot), bitter and sweet cassava, chayote(root), chufa, dasheen (taro), ginger, leren, potato, sweet potato, tanier (cocoyam), tumeric, yam bean (jicama, manoic pea) and true yam) may be planted immediately following harvest. Do not plant for food or feed any other crops not registered for use with indoxacarb for 30 days after last use.

3.4	Anticipated Exposure Pathways

Indoxacarb is registered for use on numerous agricultural crops as well as on pets, turf and inside homes.  Exposure to indoxacarb may occur from ingestion of residues in/on foods and in drinking water, and via the dermal and inhalation routes for adults using indoxacarb products in occupational and residential settings.  In addition, both adults and children may be exposed dermally or via inhalation in post-application scenarios on golf courses, lawns, and in homes; children may also be exposed orally in post-application scenarios on pets, lawns and in homes.  There is a potential for post-application dermal or inhalation exposure for workers re-entering treated fields.  
RISK ASSESSMENTS HAVE BEEN PREVIOUSLY CONDUCTED FOR indoxacarb (2009, D351087 and D365306).  The toxicity endpoints and points of departure have not changed with the exception of the addition of a long-term oral point of departure to cover residential uses of that duration and a revision to the dermal toxicity endpoint.  A re-evaluation of the dermal toxicity studies, including rat in vivo, and rat and human in vitro studies, has been performed.  Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity is therefore not expected in humans.  In addition, residential SOPs have since been revised (2012) and there are registered residential use products for which assessments have not been previously performed.  This risk assessment considers the aforementioned relevant exposure pathways based on all of the existing and proposed new uses of indoxacarb.
3.5       CONSIDERATION OF ENVIRONMENTAL JUSTICE

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.
4.0	Hazard Characterization and Dose-Response Assessment

The only new toxicity information received since the last risk assessment (2009; D351087 and D365306) is the immunotoxicity study, which was negative at doses up to 23 mg/kg/day. The toxicity endpoints have not changed with the exception of the addition of a long-term oral endpoint to cover residential uses of that duration and a revision to the dermal toxicity endpoint. The long-term oral endpoint and point of departure is the same as that selected for short- and intermediate  - term durations.  A re-evaluation of the dermal toxicity studies, including rat in vivo, and rat and human in vitro studies, has been performed. Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity is therefore not expected in humans.

4.1	Summary of Toxicological Effects

Indoxacarb products contain the enantiomeric compounds indoxacarb (S-enantiomer; DPX-KN128) and its R-enantiomer (IN-KN127).  DPX-MP062 (also referred to as MP062) is a mixture containing the S-enantiomer and its R-enantiomer at approximately a 75:25 ratio.  DPX-JW062 (also referred to as JW062) is the racemic mixture of the enantiomers. Many of the toxicity studies were conducted with JW062 (50:50).  HED's Hazard Identification Assessment Review Committee (HIARC; HED Doc No. 013528) determined that it is appropriate to use data from DPX-JW062 (50:50) to satisfy the requirements for dietary subchronic, chronic, oncogenicity and reproductive studies.  Based on previous conclusions by the HIARC, HED also accepted the same rationale for bridging the data from DPX-JW062 and DPX-MP062 to register DPX-KN128 formulations (S-enantiomer only; no R-enantiomer).

The toxicity profiles for KN128, MP062 and JW062 in rats, mice and dogs with both subchronic and chronic oral exposures were qualitatively similar.  Dermal subchronic exposure in the rat also resulted in a similar profile.  The toxic signs occurred at similar doses and with a similar magnitude of response, with females generally being more sensitive than males.  The endpoints that most frequently defined the lowest-observed-adverse-effect-level (LOAEL) were non-specific, and included decreases in body weight, weight gain, food consumption and food efficiency.  These compounds also affected the hematopoietic system by decreasing the red blood cell count, hemoglobin and hematocrit in rats, dogs and mice.  It was frequently accompanied by an increase in reticulocytes in all three species and an increase in Heinz bodies (dogs and mice only).  None of these signs of toxicity appeared to get worse over time.  In one subchronic rat study, the parameters appeared to return to normal levels following a four-week recovery period.  High doses in the rats and mice also sometimes caused mortality.

Neurotoxicity was observed in rats and mice but at higher doses (>100 mg/kg/day) than the hematologic effects (3.3 mg/kg/day) on which the risk assessments are based.   Neurotoxicity was characterized by one or more of the following symptoms in both male and female rats and mice:  weakness, head tilting, and abnormal gait or mobility with inability to stand, ataxia.  There was possible evidence of lung damage in the acute inhalation studies with both MP062 and JW062.  Subchronic (28 days) inhalation toxicity on indoxacarb in rats was characterized by increased spleen weights, increased pigmentation and hematopoiesis in the spleen, and hematological changes.

There was no evidence of carcinogenicity in either the rat or mouse in acceptable studies (JW062).  JW062 was not mutagenic in a complete battery of mutagenicity studies. There was also no evidence of mutagenicity with either KN128, or MP062.  Therefore, KN128, MP062 were classified as "not likely" to be carcinogenic in humans by all relevant routes of exposure.

In rats, both JW062 and MP062 were rapidly absorbed and eliminated following oral administration.  The metabolite profile for DPX-JW062 was dose dependent and varied quantitatively between males and females.  Differences in metabolite profiles were also observed for the different label positions. Fat tissue contained the greatest level of radioactivity and, for both compounds, was greater in female rats.  Both MP062 and JW062 were extensively metabolized and the metabolites were eliminated in the urine, feces, and bile.  All of the biliary metabolites appear to undergo further biotransformation in the gut. 

A quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day. The rat 28-day dermal study had a wide dose spacing at the lowest two doses (i.e. 50 mg/kg/day and 500 mg/kg/day), thus the rat NOAEL value of 50 mg/kg/day may be well below the no-effect dose in both rats and humans. The rat in vivo dermal absorption was 4.91%, with results from an acceptable guideline study.  In comparison, the ratio of the LOAELs from the rat developmental study and the rat 28-day dermal study of similar durations estimates the rat dermal absorption to be a much lower value of 0.8% (i.e. 100 x 4 mkd/500 mkd), with the rat dermal absorption typically multiple times higher than humans.  Based on the in vitro dermal absorption data for human skin and rat skin, the rat dermal absorption was 17.5X higher than human dermal absorption, thus the calculated indoxacarb internal dose would be much higher in rats than humans. Specifically for indoxacarb, the rat in vitro absorption was 15.2% and human in vitro absorption was 0.87%. Therefore, the dermal triple pack data was utilized to refine the dermal POD from the rat sub-chronic dermal study. Using the NOAEL value of 50 mg/kg/day from the route-specific 28-day dermal study in rats and the 17.5x ratio of human skin to rat skin absorption, the equivalent human dermal NOAEL is  875 mg/kg/day for indoxacarb (mixed isomers, 50 mkd x 15.2%/0.87%). The corresponding human dermal LOAEL value is calculated to be 8750 mg/kg/day, thus a dermal assessment is not required for indoxacarb.  Additionally, utilizing the 4.91% rat dermal absorption and the rat:human dermal absorption ratio of 17.5X, the human equivalent dermal absorption is estimated to be very low, at 0.28%, using the parallelogram method.

The toxicological database for indoxacarb is complete and adequate for dose response assessment and susceptibility determinations. The immunotoxicity study in mice did not indicate toxicity to the immune system at doses up to 23 mg/kg/day. In the 28-day inhalation study (rats) increased spleen weights, pigmentation and hematopoiesis in the spleen, and hematological changes were observed at the highest dose tested (75.6 mg/kg/day). Increased spleen weights were also observed in the 28-day dermal rat study (500 mg/kg/day). The increase in spleen weights are not considered immunological in origin but can be considered a result of the hemolytic effects, which is the mode of action of indoxacarb. Indoxacarb is currently regulated based on a NOAEL of 2.0 mg/kg/day for chronic dietary exposure (protective of hemolytic effects) and 12 mg/kg/day for acute dietary exposure.

KN128 and MP062 appear to be of similar acute oral toxicity with an acute oral toxicity category II, while JW062 appears less toxic acutely (acute oral toxicity category IV).  MP062 and JW062 had low acute inhalation toxicity.  MP062 and JW062 had moderate to low ocular irritant properties, while KN128 was practically non-irritating to the rabbit's eyes.  By the dermal route, KN128, MP062 and JW062 demonstrate low toxicity.  By the maximization test, KN128 and MP062 were considered dermal sensitizers, while JW062 was not a sensitizer.
 
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)

The following factors supporting reduction of the FQPA safety factor (SF) to 1X:  1) the hazard and exposure databases are complete; 2) there are no concerns for pre- and/or postnatal toxicity; 3) there are no residual uncertainties with regard to pre- and/or postnatal toxicity; 4) the acute neurotoxicity, subchronic neurotoxicity, and developmental neurotoxicity studies are available and all endpoints used in this risk assessment are protective of neurotoxic effects; and 5) exposures estimates will not underestimate actual exposures.

4.2.1	Completeness of the Toxicology Database

The toxicity database for indoxacarb is complete. There was no evidence of reproductive effects in the 2-generation reproduction study in rats. Teratogenicity was not observed in rats or rabbits. There was no evidence of susceptibility from either in utero or neonatal exposure to both rat and rabbit young or in the developmental neurotoxicity study in rats.  

HED has confidence that the risk assessment conducted with a reduced FQPA safety factor (1X) will provide a reasonable certainty of no harm to the safety of infants and children.

4.2.2	Evidence of Neurotoxicity

Neurotoxicity was observed in rats and mice but at higher doses (>100 mg/kg/day) than the hematologic effects (3.3 mg/kg/day) on which EPA's risk assessments are based.   Neurotoxicity was characterized by one or more of the following symptoms in both male and female rats and mice:  weakness, head tilting, and abnormal gait or mobility with inability to stand, ataxia.  Acute and subchronic neurotoxicity screening batteries were performed using MP062 in rats.  Neurotoxicity was characterized by clinical signs (depression, abnormal gait, head shake, salivation) and functional-observation battery (FOB) (circling behavior, incoordination, slow righting reflex, decreased forelimb grip strength, decreased foot splay, decreased motor activity).  However, there was no evidence of neurohistopathology in any study.  There was no evidence of increased sensitivity of offspring in the developmental neurotoxicity study using KN128.  Clinical observations, motor activity, acoustic startle habituation, and learning and memory testing were all comparable between the control and treated groups.  Mean brain weight, gross and microscopic examinations and morphometric measurements of the brain were also comparable between the controls and treated groups.

4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of susceptibility from either in utero or neonatal exposure to both rat and rabbit young with either MP062 or JW062.  There was no evidence of increased susceptibility in the young in the developmental neurotoxicity study in rats with KN128.  There was no evidence of reproductive effects in the 2-generation reproduction study in rats (JW062). No evidence of teratogenicity was observed in rats and rabbits with MP062 or JW062 nor evidence of teratogenicity in rats treated with KN128.  

4.2.4	Residual Uncertainty in the Exposure Database

The database for indoxacarb is extensive and is sufficient for characterizing toxicity and hazard.  There are no outstanding toxicity or exposure data and the FQPA safety factor is reduced to 1X. HED used partially refined assumptions in the dietary exposure assessment, including the use of percent crop treated and field trial residue values.  Upper-bound estimates of potential exposure through drinking water were used.  In addition, the residential exposure assessment was conducted such that residential exposure and risk will not be underestimated.  The aggregate exposure and risk estimates presented in this assessment will not underestimate actual exposure and risk expected based on the current and proposed use patterns.

4.3	Toxicity Endpoint and Point of Departure Selections

There have been no changes since the last risk assessment to the prior dose-response assessment, endpoint selection or cancer classification, except for the addition of the long-term incidental oral category for to residential uses of that duration and the re-evaluation of the dermal toxicity endpoint. The long-term incidental oral point of departure is the same as that selected for the short- and intermediate-term incidental oral durations. A re-evaluation of the dermal toxicity studies, including rat in vivo, and rat and human in vitro studies, has been performed. Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity is therefore not expected in humans. The endpoint selections for indoxacarb are listed in Table 4.3.1.

Acute Dietary Endpoint:  An acute reference dose (aRfD) of 0.12 mg/kg was established for the general U.S. population (including infants and children).  It was based on an acute oral neurotoxicity study in the rat.  A NOAEL of 12 mg/kg was based on decreased body weight, body-weight gain, and food consumption in females observed at the LOAEL of 50 mg/kg. The NOAEL is based on a 7% body weight decrease (in females only on day 8, but no significant differences were noted for days 1, 2 or 15). Currently, a 10% decrease in adult body weight is the threshold for an adverse effect, thus this study NOAEL is considered to be very conservative. The standard 100 UF was applied to account for interspecies extrapolation and intraspecies variation.  A FQPA SF of 1x is applicable for acute dietary risk assessment. Thus, the acute population-adjusted dose (aPAD) is equivalent to the aRfD of 0.12 mg/kg.  An endpoint of concern attributable to a single dose for females 13-49 was not identified in the database.

Chronic Dietary Endpoint:  The chronic RfD (cRfD) of 0.02 mg/kg/day was based on the:  1) rat 90-day subchronic toxicity study; 2) rat subchronic neurotoxicity study; and 3) rat chronic/ carcinogenicity study.  The selected NOAEL was 2.0 mg/kg/day.  The LOAELs for the three co-critical studies were:  1) 3.8 mg/kg/day; 2) 3.3 mg/kg/day; and; 3) 3.6 mg/kg/day.  These were based on decreased body weight, alopecia, body-weight gain, food consumption and food efficiency in females.  In addition, study #3 also had decreased hematocrit, hemoglobin and red blood cells only at 6 months in females.  Using a weight-of-evidence approach, the NOAEL for use in establishing the cRfD was 2.0 mg/kg/day).  This NOAEL was also supported by the developmental neurotoxicity study in which the systemic toxicity NOAEL was 1.5 mg/kg/day.  The standard 100 UF was applied to account for interspecies extrapolation and intraspecies variation.  A FQPA SF of 1x is applicable for chronic dietary risk assessment.  Thus, the chronic population-adjusted dose (cPAD) is equivalent to the cRfD of 0.02 mg/kg.

Short-, Intermediate-, and Long-Term Incidental Oral:  The short, intermediate and long-term endpoints were selected from the studies mentioned in the chronic dietary endpoint (see above), using the NOAEL of 2 mg/kg.  A margin of exposure (MOE) of 100 is considered adequate for incidental oral exposure risk assessment.

Short-, Intermediate-, and Long-Term Dermal Endpoints: A quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day. The rat 28-day dermal study had a wide dose spacing at the lowest two doses (i.e. 50 mg/kg/day and 500 mg/kg/day), thus the rat NOAEL value of 50 mg/kg/day may be well below the no-effect dose in both rats and humans. The rat in vivo dermal absorption was 4.91%, with results from an acceptable guideline study.  In comparison, the ratio of the LOAELs from the rat developmental study and the rat 28-day dermal study of similar durations estimates the rat dermal absorption to be a much lower value of 0.8% (i.e. 100 x 4 mkd/500 mkd), with the rat dermal absorption typically multiple times higher than humans.  Based on the in vitro dermal absorption data for human skin and rat skin, the rat dermal absorption was 17.5X higher than human dermal absorption, thus the calculated indoxacarb internal dose would be much higher in rats than humans. Specifically for indoxacarb, the rat in vitro absorption was 15.2% and human in vitro absorption was 0.87%. Therefore, the dermal triple pack data was utilized to refine the dermal POD from the rat sub-chronic dermal study. Using the NOAEL value of 50 mg/kg/day from the route-specific 28-day dermal study in rats and the 17.5x ratio of human skin to rat skin absorption, the equivalent human dermal NOAEL is  875 mg/kg/day for indoxacarb (mixed isomers, 50 mkd x 15.2%/0.87%). The corresponding human dermal LOAEL values is calculated to be 8750 mg/kg/day, thus a dermal assessment is not required for indoxacarb.  Additionally, utilizing the 4.91% rat dermal absorption and the rat:human dermal absorption ratio of 17.5X, the human equivalent dermal absorption is estimated to be very low, at 0.28%, using the parallelogram method.

Short- , Intermediate- and Long-Term Inhalation Endpoints:  The short-, intermediate-, and long-term inhalation endpoints were selected from a 28-day inhalation toxicity study in rats with MP062.  The NOAEL of 23 ug/L/day (equivalent to 6 mg/kg/day) was based on increased spleen weights, pigmentation and hematopoiesis in the spleen, hematological changes and mortality (females) seen at the LOAEL of 290 ug/L/day (equivalent to 75.69 mg/kg/day).  The effects do not seem to be progressing as study duration increases from subchronic to chronic since the NOAELs of oral subchronic and chronic studies are similar.  Therefore, use of the 28-day inhalation study is also appropriate for the long-term exposure scenario.  MOEs of 100 are considered adequate for inhalation exposure risk assessment.

Carcinogenicity:  Indoxacarb is classified as "not likely" to be carcinogenic to humans via relevant routes of exposure. Therefore, a quantitative cancer risk assessment is not required.

Table 4.3.1  Points of Departure and Toxicological Endpoints Selected for INDOXACARB for Various Exposure Scenarios.
Exposure
Scenario
Dose for Use in Risk Assessment,
UF
FQPA SF* and Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary
females 13-49 years of age
An endpoint of concern specific to females 13-49 and attributable to a single dose was not identified in the toxicity study data base, thus an acute RfD was not established.
Acute Dietary
general population including infants and children
NOAEL= 12 mg/kg
UF = 100
Acute RfD = 0.12 mg/kg

UFA= 10x
UFH=10x
FQPA SF = 1x

aPAD = 
= 0.12 mg/kg
Acute oral rat neurotoxicity study.
LOAEL = 50 mg/kg based on decreased body weight and body-weight gain in females (MP062).
Chronic Dietary
all populations
NOAEL= 2.0 mg/kg/day
UF = 100
Chronic RfD = 0.02 mg/kg/day

UFA= 10x
UFH=10x
FQPA SF = 1x 

cPAD = 
= 0.02 mg/kg/day
Weight of evidence approach was used from four studies: 
1) Subchronic toxicity study- rat (MP062).
2) Subchronic neurotoxicity study - rat (MP062).	
3) Chronic/carcinogenicity study - rat (JW062).
4) Two generation rat reproduction study (JW062).
LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 months.
Short-Term Incidental Oral
(1 to 30 days)

Oral NOAEL= 2.0 mg/kg/day

UFA= 10x
UFH=10x
FQPA SF = 1x
 
Residential LOC for MOE = 100

Occupational LOC for MOE = 100
Weight of evidence approach was used from four studies: 
1) Subchronic toxicity study- rat (MP062).
2) Subchronic neurotoxicity study - rat (MP062).	
3) Chronic/carcinogenicity study - rat (JW062).
4) Two generation rat reproduction study (JW062).
LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 months.
Intermediate-Term Incidental Oral (1- 6 months)
Oral NOAEL= 2.0 mg/kg/day

UFA= 10x
UFH=10x
FQPA SF = 1x 

Residential LOC for MOE = 100

Occupational LOC for MOE = 100
Weight of evidence approach was used from four studies:
1) Subchronic toxicity study- rat (MP062).
2) Subchronic neurotoxicity study - rat (MP062).	
3) Chronic/carcinogenicity study - rat (JW062).
4) Two generation rat reproduction study (JW062).
LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 months.
Long-Term Incidental Oral (1- 6 months)
Oral NOAEL= 2.0 mg/kg/day

UFA= 10x
UFH=10x
FQPA SF = 1x 

Residential LOC for MOE = 100

Occupational LOC for MOE = 100
Weight of evidence approach was used from four studies:
1) Subchronic toxicity study- rat (MP062).
2) Subchronic neurotoxicity study - rat (MP062).	
3) Chronic/carcinogenicity study - rat (JW062).
4) Two generation rat reproduction study (JW062).
LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 months.
Short-Term Dermal (1 to 30 days)

Intermediate-Term
Dermal (1 - 6 months)

Long-Term Dermal (> 6 Months)
A quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day.
Short-Term Inhalation (1 to 30 days)

Intermediate-Term Inhalation (1 - 6 months)

Long-Term Inhalation (> 6 Months)
Inhalation NOAEL= 23 ug/L/day (6 mg/kg/day)

UFA= 10x
UFH=10x
FQPA SF = 1x 

Residential LOC for MOE = 100

Occupational LOC for MOE = 100
28-day rat inhalation toxicity study (MP062). The LOAEL of 290 ug/L/day (75.69 mg/kg/day). is based on increased spleen weights, pigmentation and hematopoiesis in the spleen, hematological changes and mortality (females).  
Cancer (oral, dermal, inhalation)
"Not likely" to be carcinogenic to humans since no evidence of carcinogenicity in either the rat or mouse studies, and no evidence of mutagenicity.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.
5.0	Dietary Exposure and Risk Assessment 

5.1	Residues of Concern Summary and Rationale


The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1.  

Table 5.1  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression[1]
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
Indoxacarb[2] and its R-enantiomer[3]
Indoxacarb and its R-enantiomer

Rotational Crop
Indoxacarb and its R-enantiomer 
Indoxacarb and its R-enantiomer 
Livestock
Ruminant
Indoxacarb and its R-enantiomer (for all)
Metabolite IN-MP819 (for milk only)
Indoxacarb and its R-enantiomer 


Poultry
Indoxacarb, its R-enantiomer, and the metabolites IN-JT333, IN-JU873, IN-KB687, IN-KG433, IN-KT319, 5-HO-IN-JT333, and Metabolite F
Indoxacarb, its R-enantiomer, and the metabolites IN-JT333, IN-JU873, IN-KB687, IN-KG433, and IN-KT319
Drinking Water
Indoxacarb, and the degradation products IN-JT333, IN-KG4333, IN- KT413, and IN-ML437-0H

1 Adapted from: S. Levy, D325479, 03/09/2007; and D402100, Christopher M. Koper, 11/06/2012.
[2] "Indoxacarb" in this table refers to the S-enantiomer (KN-128)
3  R-enantiomer of indoxacarb (KN-127)


5.2	Food Residue Profile

The dry bean and snap bean field trials submitted with this petition are adequate to support the proposed new uses on dry bean and succulent bean.  A sufficient number of trials were conducted on each crop at 1x the maximum proposed rate in the appropriate geographic regions with the proper representative raw agricultural commodities (RACs) being collected for analysis.  Samples were analyzed using adequate analytical methods; total indoxacarb (both S- and R-enantiomer) was measured.  Sample storage durations are supported by the available storage stability data.  The current plant-back restrictions on the label remain adequate.  Processing studies are not required for these RACs. 
 
The tolerance for dry beans covers the southern pea variety, cowpea.  Cowpea is the only dry bean crop considered for livestock feeding (cowpea seed, forage and hay).  Residue data have been submitted and a tolerance has been proposed for residues of indoxacarb on dry bean (cowpea) forage.  However, residue data for cowpea hay have not been submitted nor has a tolerance been proposed.  HED is recommending establishment of a tolerance for indoxacarb on cowpea hay of 100 ppm. The recommended hay tolerance is derived from the highest forage residue to which a drying factor has been applied.  Specifically, the 32 ppm residue is multiplied by the ratio of maximum percent dry matter for hay and forage (32 *86/30=92).  This results in a very conservative tolerance level for indoxacarb on cowpea hay which was considered in dietary burden calculations.  Cowpea (forage and hay) are fed to dairy cattle.  

For snap beans (with pods), the total combined residues of indoxacarb (KN128 and KN127) ranged from 0.04 ppm to 0.59 ppm.  Residues in whole snap bean plants/foliage were found between 1.3 ppm and 32 ppm.  For dry bean seeds, total residues ranged from <0.01 ppm to 0.069 ppm.  Adequate residue decline data was generated with snap beans and dry beans indicating that residues of indoxacarb decline fairly rapidly after treatment.  

Residue data for cranberries and grapes was previously evaluated and considered acceptable.  The data for cranberries is adequate to support the tolerance for low growing berry subgroup 13-07H.  The use pattern of the grape field trial correspond to the same single application rate and PHI of the proposed use pattern for small fruit vine climbing subgroup 13-07F but a higher maximum seasonal application rate (0.44 lb ai/A instead of 0.22 lb ai/A) and shorter RTI (5-days instead of 21-days).  Since the single application rate and PHI are similar and higher residues than the proposed tolerance would not be expected, it is recommended to use available residue data without applying a scaling factor to adjust the residue level.  The existing cranberry and grape residue data are considered adequate to recommend tolerances for the corresponding crop subgroups.

5.3	Water Residue Profile

EFED performed a Tier II drinking water assessment (DWA) which utilized modeling to estimate the surface water and groundwater concentrations of indoxacarb in drinking water source water (pre-treatment) resulting from use on vulnerable sites (D402100, 11/6/13, Tier II Drinking Water Assessment for the New Use Registration of Indoxacarb on Dry Beans, Snap Beans, Small Fruit Vine Climbing Subgroup 13-07F and Low-Growing Berry Subgroup 13-07H).  No monitoring data were available for indoxacarb at the time of this assessment.  Based on the Metabolism Assessment Review Committee (MARC) recommendations, a Total Toxic Residue (TTR) approach was used for the parent indoxacarb and the degradation products with toxicological concern (IN-JT333, IN-KG4333, IN- KT413, IN-ML437-0H) for the drinking water assessment.    

The recommended estimated drinking water concentrations (EDWCs) for the human health risk assessment are based on highest predicted value for surface water and groundwater (Table 5.3), which are based on two applications of 0.11 lbs. a.i./acre/season on cranberry and four applications of 0.11 lbs. a.i./acre on beans and berries respectively.  For acute and chronic dietary risk assessments, respectively, the 1-in -10 year peak (59.26 ppb) and the 1-in -10 year annual average (18.48 ppb) indoxacarb residues of concern in surface water from the Provisional Cranberry Model (PCM) were used.


Table 5.3  Recommended Estimated Drinking Water Concentrations (EDWCs)[1] for Surface Water and Ground Water  - Indoxacarb and Degradation Products
                             Drinking Water Source
                                     Model
                                   Scenario
                                   Method[2]
                                   Maximum 
                               Application Rate
                        (interval between applications)
                          1-in-10 year acute (ug/L)
                         1-in-10 year chronic (ug/L)
                           30- year average (ug/L)
                                 Surface Water
Provisional Cranberry Model
Cranberry
                                      PCM
2 app @ 0.11 lb a.i./acre
                                     59.26
                                     18.48
                                     18.48
                                 Ground Water
SCI-GROW
(Beans, Berries)
                                      --
4 app @ 0.11 lb a.i./acre
                                     0.33
                                     0.33
                                     0.33
1 For surface water (PRZM/EXAMS), EDWC values adjusted with a Percent Cropped Area (PCA) factor of 0.87.  For ground water (SCI-GROW), no PCA adjustment was utilized.  
2  PCM = The Provisional Cranberry Model (PCM) is a provisional refinement to the Tier I Rice Model (v1.0, May 8, 2007).   Refinements include the addition of simple degradation processes in dry and flooded conditions and a water depth of twelve inches, rather than the water depth of four inches used in the rice model. These modifications allow estimation of screening-level peak and annual mean EDWCs of residues of concern that may occur in untreated surface water used as drinking water following use on cranberries.


5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Refined acute probabilistic and chronic dietary (food plus drinking water) exposure assessments were conducted for the existing and proposed food uses of indoxacarb (I. Negrón-Encarnación, 5/1/13, D408983, Indoxacarb Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13-07F and Low Growing Berry Subgroup (except strawberry) 13-07H).  A cancer dietary exposure assessment was not conducted for indoxacarb because indoxacarb has been classified as "not likely to be carcinogenic."  The dietary assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) Version 3.16, which uses food consumption data from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) from 2003 to 2008.  Anticipated residues (ARs) for all registered and proposed food commodities were based on field trial data (FTD), and for some crops tolerance level residues were used.   Residue estimates for many current uses were further refined using percent crop treated (%CT) data.  Available processing data for indoxacarb were used to refine ARs for apples/pears (juice), potato (dry, chips), cotton (oil), tomato (paste and puree), peanut (oil), soybean (oil), grapes (raisin and juice), prunes (dried), and mint (oil), and other commodities where translation was applicable.  DEEM-FCID (ver. 7.81) default processing factors (PFs) were assumed for all other processed commodities.

EDWCs were provided by EFED (C. Koper, D402100, 11/06/12) and incorporated directly into the DEEM-FCID analyses.  Both the acute and chronic analyses were conducted using estimated surface water residues generated using the Provisional Cranberry Model.

For acute and chronic assessments, HED is concerned when dietary risk exceeds 100% of the aPAD and cPAD, respectively.  The DEEM-FCID(TM) analyses estimate the dietary exposure of the U.S. population and various population subgroups:  all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, adults 20-49, and adults 50+ years.  

5.4.2	Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates (BEAD Screening Level Usage Analysis (SLUA), 10/12/12) were used in the acute dietary risk assessment for the following crops that are currently registered for indoxacarb:  apples: 10%; broccoli: 70%, cabbage: 35%; cauliflower: 60%; cherries: 2.5%; lettuce: 40%; peaches: 2.5%; peanuts: 10%; pears: 2.5%; potatoes: 2.5%; soybeans: 2.5%; spinach: 5%; sweet corn:  10%; tomatoes: 40%.  The following average percent crop treated BEAD estimates were used in the chronic dietary risk assessments for the following crops that are currently registered for indoxacarb:  apples: 5%; broccoli: 50%, cabbage: 25%; cauliflower: 40%; celery: 5%; cherries: 1%; grapes: 1%; lettuce: 10%; peaches: 2.5%; peanuts: 2.5%; pears: 1%; potatoes: 1%; soybeans: 1%; spinach: 2.5%; sweet corn:  2.5%; tomatoes: 20%.  For all other crop commodities, including the proposed uses (dry bean, succulent bean and small fruit vine climbing subgroup (except kiwifruit) 13-07F and low growing berry subgroup (except strawberry) 13-07H), 100% of the crop treated was assumed.

5.4.3    Acute Dietary Risk Assessment

Estimated acute dietary exposure, using fairly refined assumptions, to indoxacarb from food and drinking water is below HED's level of concern for all population subgroups.  Combined dietary exposure from food and drinking water at the 99.9[th] percentile of exposure is estimated to be 0.033 mg/kg/day for the overall U.S. population, equivalent to 27% of the aPAD.  The population subgroup with the highest estimated acute dietary exposure to indoxacarb is all infants, with an estimated exposure at the 99.9[th] percentile of 0.058 mg/kg/day, equivalent to 49% of the aPAD.

Results of the dietary assessments can be found in Table 5.4.5 below.

5.4.4	Chronic Dietary Risk Assessment

Estimated chronic dietary exposure, using fairly refined assumptions, to indoxacarb from food and drinking water is below HED's level of concern for all population subgroups.  Combined dietary exposure from food and drinking water is estimated to be 0.0011 mg/kg/day for the overall U.S. population, equivalent to 5.7% of the cPAD.  The population subgroup with the highest estimated chronic dietary exposure to indoxacarb is children, 1 to 2 years old, with an estimated exposure of 0.0024 mg/kg/day, equivalent to 12% of the cPAD.

Results of the dietary assessments can be found in Table 5.4.5 below.

5.4.5	Summary Table

 Table 5.4.5.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Indoxacarb
                              Population Subgroup
                                 Acute Dietary
                               (99.9 Percentile)
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
                            General U.S. Population
                                    0.032762
                                      27
                                   0.001133
                                      5.7
 
 
                         All Infants (<1 year old)*
                                    0.058294
                                       49
                                   0.001772
                                      8.9
                                      N/A
                                      N/A
                            Children 1-2 years old*
                                    0.054158
                                       45
                                   0.002381
                                      12
 
 
                             Children 3-5 years old
                                    0.046841
                                       39
                                   0.001818
                                      9.1
 
 
                            Children 6-12 years old
                                    0.035434
                                       30
                                   0.001105
                                      5.5
 
 
                             Youth 13-19 years old
                                    0.025623
                                       21
                                   0.000743
                                      3.7
 
 
                             Adults 20-49 years old
                                    0.025109
                                       21
                                   0.001036
                                      5.2
 
 
                              Adults 50+ years old
                                    0.030965
                                       26
                                   0.001165
                                      5.8
 
 
                            Females 13-49 years old
                                    0.026456
                                       22
                                   0.001037
                                      5.2
 
 
*The subpopulation(s) with the highest risk estimates are highlight in bold print.
6.0     Residential (Non-Occupational) Exposure/Risk Characterization

No new residential uses and no occupational uses at residential sites are being requested with this petition; however, there are existing residential uses (turf and spot-on pet applications) that have been previously assessed and are assessed herein to reflect updates to HED's 2012 Residential SOPs, policy changes for body weight assumptions, and a re-evaluation of the dermal toxicity of indoxacarb.  In addition, there are existing residential uses (insect control treatments of household premises; Arilon Insecticide 20% ai, EPA Reg. No. 100-1501 and  Aperion Insecticide 14.5% ai, EPA Reg. No. 352-770) which do not appear to have been previously assessed and are assessed herein. These existing uses may potentially result in handler and post-application inhalation and dermal exposures for adults and post-application dermal, inhalation, and oral exposures to children.  The risk estimates from residential exposures will impact the human health aggregate risk assessment for indoxacarb.  Note that dermal exposures resulting from residential uses are not quantitatively assessed as a dermal toxicity endpoint is not identified for indoxacarb. Only the inhalation and incidental oral exposures are assessed for the residential uses of indoxacarb.

6.1	Residential Handler Exposure

HED uses the term "handlers" to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task.  Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.  Residential handler exposure is expected to be short-term in duration.  Intermediate-term exposures are not likely because of the intermittent nature of applications by homeowners.  The indoxacarb handler assessment considers short-term inhalation exposures only since a dermal toxicity endpoint is not identified.
 
The anticipated use patterns and current labeling indicate that exposure to pesticide handlers is likely during the residential uses of indoxacarb products.  Indoxacarb use patterns and current labeling indicate several likely residential handler exposure scenarios: 

   (1) Placements of ready- to-use (RTU) bait stations.
   (2) Spot-on applications of gels (crack and crevices) for household insect control (indoor treatments). 
   (3) Spot-on treatments for the control of fleas and ticks on dogs and cats.
   (4) Broadcast, perimeter and ant mound treatment on ornamentals, trees, and lawns/turf utilizing granular and liquid formulations (outdoor treatments). 
   (5) Indoor spray applications with granular and liquid formulations for insect control on households/domestic dwellings (crack and crevice and spot directed treatments).

Indoxacarb RTU bait stations and gels products are formulated for very low application rates (e.g., 6.6 x 10[-7] lb ai/spot to 5.2 x10[-5] lb ai/placement) and are designed to be self-contained; therefore, handler contact is expected to be negligible and exposure/risk for these uses were not quantitatively assessed. The spot-on product for the control of fleas and ticks on dogs and cats is designed to be self-contained as it is applied directly from the tube to the pet with the tip of the applicator used to part the pet's hair. Therefore, handler exposure is expected to be minimal for this type of applications.  Inhalation assessments are not performed for applying pet spot-on treatments, as inhalation exposure is not expected from these uses. Therefore, a handler assessment is not performed for the indoxacarb pet spot-on treatments.

Indoxacarb liquid and granular formulations (e.g., Provaunt 1.25 SC and Advion G), are registered for use in residential lawns, recreational areas and golf courses.  Additionally, a dry flowable formulation (Provaunt Insecticide DF) is registered for use in residential lawns and recreational areas.  Even though the labels states that these products are "intended to be applied by professional commercial operators (PCO) only", this label restriction is not considered sufficient to preclude use by homeowners; therefore, these uses were assessed.  

Other granular products intended for residential treatments on ornamentals, trees, and lawns such as Chemsico Insect Bait (EPA Reg. No. 9688-217), and ant mound treatment product, Tomcat Ant Killer (EPA Reg. No. 12455-107), are also formulated at very low application rates (maximum application rate of 8 x 10 -8 lb ai/ft[2]).  MOE estimates for these uses will be well above a million, and; therefore, were not quantified. 

Two indoxacarb formulations: Arilon Insecticide 20% ai  (EPA Reg. No. 100-1501) and Aperion Insecticide 14.5% ai  (EPA Reg. No. 352-770), were identified for use in households and domestic dwellings.  Even though the labels state that both products are "intended to be applied by PCOs only", this restriction is not considered sufficient to preclude use by homeowner/residential applicators; therefore, these uses were assessed.  Although outdoor treatments are also permitted, only the indoor uses were assessed since the outdoor applications are expected to result in lower risk/exposure estimates than the indoor spray applications and the turf uses assessed.

The quantitative inhalation exposure/risk assessment developed for residential handlers for existing indoxacarb uses is based on the following scenarios:  

   (1) Mixing/loading/applying granular formulation for insect control on lawns/turf.
   (2) Mixing/loading/applying liquid flowable formulation for insect control on lawns/turf.
   (3) Mixing/loading/applying water-soluble packaging formulation for indoor spray applications with manually-pressurized hand wand (crack and crevice and spot directed treatments) for insect control in households/domestic dwellings.
   (4) Mixing/loading/applying liquid flowable formulation for indoor spray applications with manually-pressurized hand wand (crack and crevice) for insect control on households/domestic dwellings.

Residential Handler Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments.  These assumptions and factors, including application rate, body weights, unit exposure, etc. are detailed in D411342 (A. Rivera-Lupianez, 5/1/13, Indoxacarb Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Bean (dry), Bean (snap), Bean (forage), and Small Fruit Vine Climbing Subgroup 13-07F and Low-Growing Berry Subgroup 13-07H) and the 2012 Residential SOPs.

The inhalation exposure and risk estimates are presented for the residential scenarios that led to the highest exposure (i.e., backpack and manually pressurized hand wand applications of liquid sprays on turf, belly grinder application of granules on turf, and manually pressurized hand wand applications for indoor spray treatments).  Residential handler exposure scenarios for the indoxacarb S-enantiomer and its R-enantiomer 75:25 ratio mixture (KN128/KN127) formulation are summarized as follows:

KN128/KN127 (75:25 isomeric mixture):
   1. Lawn/Turf: Provaunt 1.25 SC 14.5% ai (EPA Reg. No. 352-637); a liquid formulation for use on turf (residential lawns, recreational areas, and golf courses).
   2. Lawn/Turf: Advion G 0.22% ai (EPA Reg. No. 100-1483); a granular formulation for use on turf (residential lawns, recreational areas, and golf courses).
   3. Lawn/Turf: Provaunt Insecticide DF (EPA Reg. No 100-1487); a dry flowable formulation for use on turf (residential lawns, recreational areas, and golf courses). 
   4. Indoor Spray (Crack and Crevice and Spot Treatment): Arilon Insecticide 20% ai (EPA Reg. No. 100-1501); a water-soluble packaging formulation for use on households/domestic dwellings.
   5. Indoor Spray (Crack and Crevice): Aperion Insecticide 14.5% ai (EPA Reg. No. 352-770); a liquid formulation for use on households/domestic dwellings.


Summary of Residential Handler Non-Cancer Exposure and Risk Estimates

KN128/KN127 (75:25 Isomeric Mixture) Exposure Scenarios- Lawn/Turf and Indoor Crack and Crevice/Spot-Directed Treatments:

The residential handler exposure assessment for turf (lawn) and indoor (crack and crevice and spot-directed) applications resulted in short-term inhalation MOEs that do not exceed HED's level of concern (i.e., MOEs >= 100). Table 6.1.1 presents a summary of the residential handler scenarios assessed.


Table 6.1.1.  Residential Handler Short -Term Exposure and Risk Estimates for Indoxacarb: KN128/KN127 (75:25 Isomeric Mixture)
                               Exposure Scenario
                               Level of Concern
                           Inhalation Unit Exposure 
                                  (mg/lb ai)
                          Maximum Application Rate[1]
                    Area Treated or Amount Handled Daily[2]
                                  Inhalation
                                       
                                       
                                       
                                       
                                       
                              Dose (mg/kg/day)[3]
                                    MOE[4]
                        Mixer/Loader/Applicator (M/L/A)
                                  Lawns/Turf
Provaunt Insecticide DF -Dry Flowable Formulations  -  EPA Reg. No. 100-1487 (Former: EPA Reg. No. 352-716)
Mannually Pressurized Hand Wand/
Backpack
                                      100
                                      1.1
                               0.0065 lb ai/gal 
                                     5 gal
                                    0.00045
                                    13,000
         Provaunt 1.25 SC-Liquid Formulations  - EPA Reg. No. 352-637
Backpack
(liquid)

                                      100
                                     0.14
                               0.0065 lb ai/gal
                                     5 gal
                                   0.000057
                                    105,000
Manually Pressurized Hand Wand
(liquid)

                                      100
                                     0.018
                                       
                                       
                                 7.3 x 10[-6]
                                    825,000
Advion G- Granular Formulations- EPA Reg. No. 100-1483 (Former: EPA Reg. No. 352-651)
Belly grinder
(granules)
                                      100
                                     0.039
                             0.000013 lb ai/ft[2]
                                  1,200 ft[2]
                                 7.6 x 10[-6]
                                    785,000
     Crack and Crevice and Spot-Directed Treatments (Indoor Environments)
Arilon Insecticide 20% ai  - EPA Reg. No. 100-1501 (Former: EPA Reg. No. 352-776)
Manually Pressurized Hand Wand (water dispersible packets)

                                      100
                                      1.1
                                0.011 lb ai/gal
                                       
                             (0.00004 lb ai/ft[2])
                                    0.5 gal
                                   0.000076
                                    80,000
             Aperion Insecticide 14.5% ai  - EPA Reg. No. 352-770
Manually Pressurized Hand Wand
(liquid)

                                      100
                                      1.1
                                0.010 lb ai/gal
                                       
                             (0.00004 lb ai/ft[2])
                                    0.5 gal
                                    0.00006
                                    86,000
1.	Based on registered label (EPA Reg. No.). Application rates = maximum application rates from labels (EPA Reg. No.: 352-637, 100-1487, 100-1483, 100-1501, 100-1498, and 352-770). The application rate for all mixture formulations have been adjusted by a 4/3 factor to account for 4 parts of total (S- and R-) indoxacarb for every 3 parts of S- indoxacarb.
2.	Based on HED's 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).
3.	Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) / Body Weight (kg).
4. Inhalation MOE = Inhalation NOAEL (6 mg/kg/day) / Inhalation 

6.2	Residential Post-Application Exposure 

There is the potential for post-application exposure for individuals exposed as a result of being in an environment, such as on a lawn or floor or petting an animal, that has been previously treated with indoxacarb.  Residential post-application exposures (e.g., exposures from treated lawns and indoor environments), are generally considered to be intermittent and short-term in duration.  However, because of the preventative nature of pet products and the potential for extended usage in more temperate parts of the country, the residential post-application exposures to treated pets may be short-, intermediate-, or long-term in duration.  The post-application assessment considers inhalation and oral exposures only since a dermal toxicity endpoint is not identified for indoxacarb. The toxicological endpoints and points of departure are the same for each route of exposure regardless of duration.

The quantitative exposure/risk assessment for residential post-application exposures is based on the following scenarios:  

   (1) Treated pets (dogs and cats): children 1 to < 2 years old (incidental oral);
   (2) Treated turf:  children 1 to < 2 years old (incidental oral);
   (3) Crack and crevice indoor and spot-directed spray applications: inhalation (adults and young children 1 to <2 years old), and incidental oral (young children 1 to <2 years old) exposures.

It should be noted that post-application exposures (incidental oral) from treated golf courses were not quantified since youth old enough to play golf are not expected to exhibit significant hand-to-mouth behavior. Furthermore, the residential lawn assessment provides the highest estimate of potential exposure from turf applications and is protective of any exposures to indoxacarb turf treatment scenarios.

The lifestages selected for each post-application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs.  These lifestages are not the only lifestages that could be potentially exposed for these post-application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

Two indoxacarb formulations: Arilon Insecticide 20% ai  (EPA Reg. No. 100-1501) and Aperion Insecticide 14.5% ai  (EPA Reg. No. 352-770), were identified for insect control in households and domestic dwellings.  Even though outdoor treatments are also permitted; outdoor applications are expected to result in lower risk/exposure estimates than indoor spray treatments or turf uses.  Therefore, only the indoor uses that would potentially lead to the highest post-application exposures were assessed (i.e., exposure from contact with carpet and hard surfaces resulting from surface directed spray applications).  It should be noted that even though neither of these labels have been previously assessed, only the Arilon formulation was assessed for post-application exposures. The Aperion Insecticide formulation, a termiticide, was not assessed for post-application exposure since the label use pattern limits indoor uses to "localized spot treatments" such as crawlspaces, basements or attics and post-application exposures are not likely.  Furthermore, the assessment of the Arilon formulation, which is applied at a higher application rate than the Aperion formulation, is assumed to provide a conservative surrogate assessment for the Aperion uses. 

Residential Post-Application Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential post-application risk assessment for indoxacarb.  Two chemical specific animal petting studies (MRIDs 47834502 and MRID 48010801) were used to estimate transferable residues for the incidental oral exposure for children for the treated pet scenario.  A chemical specific (indoxacarb) turf transferable residue (TTR) study (MRID 4679820) was used to estimate incidental oral exposure for children for the turf (liquid formulations) scenarios.  A default TTR was used for the turf granular formulation scenario since the available chemical specific study was only for the liquid formulation.  The assumptions and factors, as well as those regarding application rate and timing, body weights, etc., are detailed in D411342, 5/1/13, and the 2012 Residential SOPs.

Combining Exposure and Risk Estimates
Since inhalation and incidental oral exposure routes share a common toxicological endpoint (i.e., hematological changes), risk estimates have been combined for those routes. Incidental oral ingestion (i.e., hand-to-mouth, object-to-mouth, and soil ingestion (where appropriate)) for a given residential scenario should be considered inter-related and it is likely that they occur interspersed amongst each other across time.  Combining all of these incidental oral exposure estimates with the inhalation exposure would be overly-conservative because of the conservative nature of each individual incidental oral assessment.  Therefore, the post-application exposure scenarios that were combined for children 1 < 2 years old are the inhalation and hand-to-mouth (the highest incidental oral exposure assessment) for the indoor surfaces directed spray applications.  This combination is considered protective of children's exposure to indoxacarb from residential uses.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates
For the purpose of presentation of post-application exposure and risk estimates, the exposure scenarios for the KN128 (S-enantiomer only) formulation and the KN128/KN127 (75:25 S-and R- enantiomer mixture) formulations have been separated.  

KN128 (S-enantiomer only):
   1. Treated Pets: Actyvil Liquid RTU Formulation for spot-on treatments on cats (EPA Reg. No. 773-93) and dogs (EPA Reg. No 773-94).

KN128/KN127 (75:25 S- and R- isomeric mixture):
   1. Lawn/Turf: Provaunt 1.25 SC 14.5% ai (EPA Reg. No. 352-637); a liquid formulation for use on turf (residential lawns, recreational areas, and golf courses).
   2. Lawn/Turf: Advion G 0.22% ai (EPA Reg. No. 100-1483); a granular formulation for use on turf (residential lawns, recreational areas, and golf courses).
   3. Lawn/Turf: Provaunt Insecticide DF (EPA Reg. No 100-1487); a dry flowable formulation for use on turf (residential lawns, recreational areas, and golf courses).
   4. Indoor Spray (Crack and Crevice and Spot-Directed Treatments): Arilon Insecticide 20% ai (EPA Reg. No. 100-1501); a water-soluble packaging formulation for use on households/domestic dwellings.

KN128 Exposure Scenarios

Treated Pets Scenarios

A summary of the children short-, intermediate- and long-term (ST/IT/LT) exposure and risk estimates from treated pet (cat and dog) scenarios are shown in Table 6.2.1.  Incidental oral (hand to mouth) risk estimates for children for the indoxacarb pet spot-on liquid formulations do not exceed HED's level of concern (MOEs >= 100). 


Table 6.2.1. Residential Post-application ST/IT/LT (Non-Cancer) Exposure and Risk Estimates for Indoxacarb: KN128 formulation 
                                   Lifestage
                      Post-application Exposure Scenario
                                 Application 
                                   Rate [a]
                                       
                                       
                                       
                           Dose [b][,c] (mg/kg/day)
                                   MOEs [d]
                                Combined MOEs 
                                       
                               Route of Exposure
                                   Use Site
                                       
                                       
                                       
                                       
            Liquid Spot-on Treatments Formulations (Companion Pets)
                          Child 1 to < 2 years old
                                  Oral (HTM)
                                     Cats
                                115 (mg ai/pet)
                                    0.0012
                                     1,600
                                      NA
                                       
                                       
                                     Dogs
                               900  (mg ai/pet)
                                    0.0024
                                      830
                                       
a	Based on application rates (AR) from labels that led to highest dermal exposure: Actyvil Liquid RTU Formulation for spot-on treatments on cats (EPA Reg. No. 773-93) and dogs (EPA Reg. No 773-94) 
b. Fraction Application Rate (Far) = Peaked amount of indoxacarb removed as a fraction of dose applied from MRIDs:  48135325 and 48010801; Far = 0.0255 (dogs); 0.0124 (cats).
c.  Hand-to-Mouth Dose (mg/kg/day)  = [(Hand Residue Loading (mg/cm[2]) x Fraction of Hand Mouthed x Surface Area of 1 Hand (150 cm[2]) x Exposure Time (1.5 hrs/day) x # of Replenishment Intervals/hr (4 int/hr) x (1-((1-Saliva Extraction Factor (0.5))^(Number of Hand-to-Mouth Events per Hour (13.9 events/hr) ) /  ( # of Replenishment Intervals/hr))]  / Body Weight (11 kg child 1 < 2 years old)]
d.	Oral MOE = NOAEL (2 mg/kg/day; KN128)/ Oral Dose (mg/kg/day)


KN128/KN127 (75:25 Isomeric Mixture) Exposure Scenarios

Turf Scenarios

A summary of the children short-term post-application exposure and risk estimates from the turf scenarios is shown in Table 6.2.2.  Children's short-term incidental oral risk estimates (for both liquid and granular formulations) do not exceed HED's level of concern (MOEs >= 100).  

Indoor Surfaces Directed Spray Scenarios (Crack and Crevice and Spot-Directed Treatments)

A summary of the adult and children short-term post-application exposure and risk estimates from the indoor spray uses of indoxacarb is shown in Table 6.2.2.  All adult and children inhalation risk estimates do not exceed HED's level of concern (MOEs >= 100).  For children, the incidental oral risk estimates for crack and crevice treatments do not exceed HED's level of concern (MOEs >= 100). However, for spot-directed treatments, oral (hand-to-mouth) exposure estimates alone for children 1 to < 2 years old exceed HED's level of concern (MOE = 32).  For crack and crevice only scenarios the combined inhalation and incidental oral risk estimates for children 1 to < 2 years old are not of concern (MOEs >= 100).  




Table 6.2.2.  Residential Post-application ST (Non-Cancer) Exposure and Risk Estimates for Indoxacarb:  KN128/KN127 (75:25 Isomeric Mixture).
                                   Lifestage
                      Post-application Exposure Scenario
                                 Application 
                                  Rate [a, b]
                                   (lb ai/A)
                            Dose c, d, (mg/kg/day)
                              MOEs [e, f, g, h,]
                                Combined Routes
                    (X indicates included in Combined MOE)
                               Combined MOEs [i]
                                       
                               Route of Exposure
                                   Use Site
                                       
                                       
                                       
                                       
                                       
                              Lawn/Turf Scenarios
Provaunt 1.25 SC-Liquid Formulations and Provaunt Insecticide DF -Dry Flowable Formulations
                            Child 1 < 2 year old
                                     Oral 
                                 Hand-to-Mouth
                                 0.22 lb ai/A
                          (0.29 lb ai total isomer/A)
                                    0.0042
                                      480
                                       
                                      NA
                                       
                                       
                                Object-to-Mouth
                                       
                                    0.0001
                                    20,000
                                       
                                       
                                       
                                       
                                Soil Ingestion
                                       
                                  9.9 x 10-6
                                    200,000
                                       
                                       
                       Advion G- Granular Formulations 
                            Child 1 < 2 year old
                                    Oral  
                                 Hand-to-Mouth
                                 0.44 lb ai/A
                         (0.586 lb ai total isomer/A)
                                    0.0009
                                     2,300
                                       
                                      NA
                                       
                                       
                                Object-to-Mouth
                                       
                                    0.00005
                                    40,000
                                       
                                       
                                       
                                       
                                Soil Ingestion
                                       
                                   2 x 10-5
                                    100,000
                                       
                                       
                                       
                                       
                          Episodic Granular Ingestion
                                       
                                     0.060
                                      200
                                       
                                       
Crack and Crevice and Spot Directed Treatments (Indoor Surface Directed Sprays Scenario)
                          Arilon Insecticide 20% ai  
                                     Adult
                                  Inhalation
                            Surface directed sprays
                                       
                      0.00004 lb ai  total isomer /ft[2]
                                  2.2x 10[-8]
                                  2.6 x 10[8]
                                       
                                      NA
                           Child 1 < 2 years old
                                     Oral
           Hand-to-Mouth from carpets (crack and crevice treatment)
                                       
                                    0.0126
                                      160
                                       X
                                      160
                                       
                                       
             Hand-to-Mouth from carpets (spot directed Treatment)
                                       
                                    0.0632
                                      32
                                       
                                       
                                       
                                       
          Object-to- Mouth from carpets (crack and crevice treatment)
                                       
                                     0.002
                                     1000
                                       
                                       
                                       
                                       
            Object-to- Mouth from carpets (spot directed Treatment)
                                       
                                     0.008
                                      250
                                       
                                       
                                       
                                  Inhalation
                            Surface directed sprays
                                       
                                  9.6x 10[-8]
                                  6.2x 10[7]
                                       X
                                       
a.  Based on application rates (AR) from labels that led to highest dermal exposure: 
    AR = maximum application rates from labels (EPA Reg. No.: 352-637, 100-1483, 100-1501 and 352-770). The application rate for all mixture formulations have been adjusted by a 4/3 factor to account for 4 parts of total (S- and R-) indoxacarb for every 3 parts of S- indoxacarb.
b. Turf Transferable Residue (TTR)  -  The highest average value (0.023 ug/cm[2]) from NY, NC and CA site study (MRID 46798201) was used for the Provaunt 1.25 SC and Provaunt Insecticide DF formulations assessment. The TTR value was adjusted to 0.031 ug/cm[2] to account for 4 parts of total (S- and R-) indoxacarb for every 3 parts of S-indoxacarb. A default predicted Day 0 TTR value (0.013 ug/cm2) was used for Advion G.
c.  Turf Scenarios Dose Equations
     Hand-to-Mouth Dose (mg/kg/day) = [(Hand Residue Loading (mg/cm[2]) x Fraction of Hand Mouthed x Surface
    Area of 1 Hand (150 cm[2]) x Exposure Time (1.5 hrs/day) x # of Replenishment Intervals/hr (4 int/hr) x (1-((1-Saliva
    Extraction Factor (0.5))^(Number of Hand-to-Mouth Events per Hour (13.9 events/hr)  /  ( # of Replenishment 
    Intervals/hr))]  / Body Weight (11 kg child 1 < 2 years old)]
    
    Object-to-Mouth Dose (mg/kg/day) = object residue loading (ug/cm[2]) x unit conversion factor (0.001 mg/ug) x
    object surface area mouthed / event (10 cm[2]/event) x exposure time (1.5 hrs/day) x # replenishment intervals/hr (4 
    int/hr) x (1-((1- saliva extraction factor (0.50))^(# Object-to-Mouth Events/hr (8.8 events/hr) / # replenishment 
    intervals/hr)) / body weight (11 kg).
 
    Soil Ingestion Dose (mg/kg/day) = soil residue (ug/g) x ingestion rate (50 mg/day) x conversion factor (0.000001 
    g/ug) / body weight (11 kg).

   Episodic Granular Ingestion Dose (mg/kg/day) = [(ingestion rate of dry pesticide formulation (g/day) * fraction of ai 
    in dry formulation (unitless) * weight unit conversion factor (1,000 mg/g)] / body weight (11 kg).	

d. Crack and Crevice and Spot Directed Treatment Scenarios Dose Equations	


    Hand-to-Mouth Dose (mg/kg/day) = [(Fraction of ai on Hands (0.15) x Dermal Exposure (0.14)) / (2 x Surface Area
    of 1 hand (150 cm[2]) ) x Fraction of Hand Mouthed  (0.13) x Exposure Time per Day (carpet, 4; hard  surfaces, 2 
    hours hrs/day) x # of Replenishment Intervals per Hour (4 int/hr) x (1-((1-Saliva Extraction Factor (0.5)) ^ (Number 
     of Hand-to-Mouth Events per Hour (20 events/hr)  /  ( # of Replenishment Intervals per Hour (4)))]  / Body 
    Weight (child, 11 kg)]

    Object-to-Mouth Dose (mg/kg/day) = [(Deposited Residue (1.0 μg/cm[2]) x Fraction of Residue Transferred to an  Object(carpet, 0.06; hard  surface, 0.08)) x Unit Conversion Factor (0.001 mg/ug) x Object Surface Area Mouthed  (10 cm[2]/event) x Exposure Time (carpet, 4; hard surface, 2 hrs/day) x # Replenishment Intervals per Hour (4 int/hr) x (1-((1- Saliva Extraction Factor (0.50)) ^ (# Object-to-Mouth Events per Hour (14 events/hr) / # Replenishment Intervals per Hour (4/ hr))) / Body Weight (child, 11 kg)]

   Inhalation Daily Dose (mg/kg/day) = [(Inhalation Rate (0.64, adult; 0.33 child m[3]/hr) x Mass of Active Ingredient Applied (298 mg ai)) / (Air Exchanges per Hour (0.45/hr) x Volume of Room (33 m[3])) / [1  -  ((Air Exchanges per Hour (0.45/hr) x e ^ (-First Order Decay Rate (2.1 x 10[-5]) x Exposure Time (hr)))  -  (First Order Decay Rate (2.1 x 10[-5]) x e ^ (-Air Exchanges per Hour (0.45/hr) x Exposure Time (hr))) / (Air Exchanges per Hour (0.45/hr)  -  First Order Decay Rate (2.1 x 10[-5]))] / Body Weight (child, 11 kg)]

f.  Inhalation MOE = Inhalation NOAEL (6 mg/kg/day;) / Inhalation Dose (mg/kg/day).
 g.  Oral MOE = NOAEL (2 mg/kg/day) / Oral Dose (mg/kg/day)
 h.  Episodic Granular Ingestion MOE = NOAEL (12 mg/kg/day;) / Episodic Granular Ingestion Dose (mg/kg/day)
 i. Combined MOE = 1 / [(1/incidental oral MOE) + (1/ Inhalation MOE)], where applicable.

6.3	Residential Risk Estimates for Use in Aggregate Assessment

Tables 6.3.1 and 6.3.2 show residential risk estimates that can be used in the aggregate assessment for indoxacarb. The scenarios and lifestages resulting in the highest residential exposures are selected for use in the aggregate assessment and are considered protective of other scenario exposures (those risk estimates in bold in the tables are included in the aggregate assessments).  

For indoxacarb, there are potential residential exposures from indoor applications, outdoor/lawn applications and pet applications.  Each of these scenarios are assessed using high-end, conservative assumptions (e.g., maximum application rate, high-end area treated or amount handled, no dissipation of residue over the exposure duration, etc).  Because each scenario reflects the use of high-end inputs, the individual residential scenarios are not combined for use in the aggregate; rather, the scenario resulting in the highest exposure is aggregated with food/water to be protective of all possible residential scenarios.  Multiple residential scenarios are also not combined in many cases because available survey data indicate that the probability of multiple residential products (e.g., a pet care product and an indoor product), containing the same active ingredient, being used on the same day is very low.

Exposure from the pet spot-on use is assumed to occur over short-, intermediate-, and long-term durations.  As is the case for all the residential exposure scenarios, the long-term exposure assessment for the pet uses are conducted using high-end, conservative inputs (e.g., maximum application rates, day-0 residue values, no dissipation of residues over time) resulting in a very conservative long-term exposure/risk estimate that would not be appropriate to include in the short- term aggregate assessment as "background" exposure.

Based on the potential residential scenarios for indoxacarb and the considerations noted above, the following is a list of the recommended residential scenarios for the indoxacarb aggregate assessments: 

   * The short -term residential exposure for use in the adult aggregate assessment reflects residential handler inhalation exposures from mixer/loader/applicator scenarios for dry flowable formulations treatments on turf via manually pressurized hand wand or backpack.
   * The short -term residential exposure for use in the child (1<2 years) aggregate assessment reflects combined post-application inhalation and incidental oral (hand-to-mouth) exposures from indoor crack and crevice treatments with surface directed sprays. The incidental oral (hand-to-mouth) risk estimate for the indoor spot-directed treatments was of concern by itself and is not included in the aggregate.
   * The intermediate- and long -term residential exposure for use in the child (1<2 years old) aggregate assessment reflects post-application incidental oral (hand-to-mouth) exposures from treated pets.
   



Table 6.3.1.  Residential Exposures for the Indoxacarb Aggregate Assessment (KN128; Pet Treatment).
                                   Lifestage
                              Residential Handler
                         Residential Post-application 
                                       
                               Dose (mg/kg/day)
                                      MOE
                                Dose (mg/kg/day
                                      MOE
                                       
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                         Short - Term (Pet Treatment) 
Adult 
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
Child 1<2
                                      N/A
                                      N/A
                                      N/A
                                    0.0024
                                    0.0024
                                      N/A
                                      N/A
                                      830
                                      830
                  Intermediate- or Long-Term (Pet Treatment) 
Adult 
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
                                      N/A
Child 1<2
                                       
                                      N/A
                                      N/A
                                    0.0024
                                    0.0024
                                      N/A
                                      N/A
                                      830
                                      830
N/A= not applicable


Table 6.3.2.  Residential Exposures for the Indoxacarb Aggregate Assessment (KN128/127; Turf or Indoor Use)
                                   Lifestage
                          Residential Handler (Turf)
                   Residential Post-application (Indoor Use)
                                       
                               Dose (mg/kg/day)
                                      MOE
                               Dose (mg/kg/day)
                                      MOE
                                       
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                       Short-Term Term (Turf or Indoor)
Adult 
                                      N/A
                                    0.00045
                                    0.00045
                                      N/A
                                    13,000
                                    13,000
                                      N/A
                                 2.2 x 10-[8]
                                      N/A
                                 2.2 x 10-[8]
                                      N/A
                                 2.7 x 10 [8]
                                      N/A
                                 2.0 x 10 [8]
Child 1<2
                                      N/A
                                      N/A
                                 9.6 x 10-[8]
                                     .0126
                                    0.0126
                                      N/A
                                 6.2 x 10 [7]
                                      160
                                      160
N/A= not applicable
1. Turf Use Scenario
2. Indoor Environment Scenario


6.4	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for indoxacarb at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for indoxacarb.

6.5	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for indoxacarb. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of indoxacarb drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers and there were no risk estimates of concern. This exposure scenario is representative of high-end inhalation (drift) exposure and may be considered protective of indoxacarb outdoor agricultural and commercial post-application inhalation exposure scenarios.  

Furthermore, residential turf uses were quantitatively assessed as part of this risk assessment; risk estimates addressed in the residential turf assessment provide a worst case estimate of potential exposure from spray drift.  It is noted that the 0.44 lb ai/acre application rate for turf was modeled to estimate post-application residential exposure of children.  As this rate is equal to or higher than agricultural application rates for indoxacarb, this scenario is protective of any exposure of children via spray drift from agricultural indoxacarb applications.
7.0      Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Based on the existing and newly proposed uses of indoxacarb, exposures can occur both from dietary sources (food and water) and in residential settings.  Uses of indoxacarb that may result in residential exposures include indoor treatments, spot-treatment of companion animals, and turf (lawn uses and golf courses).
 
The aggregate risk assessments are intended to be representative of exposures that are likely to co-occur.  The scenarios expected to result in the highest exposures are used as representative scenarios for the aggregate assessment and are considered protective of other scenarios. The lifestages selected for the aggregate assessments represent the population subgroups expected to be the most highly exposed for each scenario.  For more information on the exposure scenarios selected for aggregate assessment, see Section 6.3 above.

7.1	Acute Aggregate Risk

Typically, HED does not consider residential exposures when assessing acute aggregate risk unless such exposures can be characterized as a series of single-day exposures, which is not the case for indoxacarb.  Therefore, acute aggregate risk estimates for indoxacarb are equivalent to the acute dietary (food and drinking water) risk estimates (Section 5.4) and are below HED's level of concern.  

7.2     Short- Term Aggregate Risk

The short- term aggregate risk for indoxacarb includes background contribution from dietary (food and drinking water) exposure plus the highest short- term residential exposures for adults and children (Table 7.2.1 below).  The short-term aggregate assessment for adults includes residential exposure from mixing, loading and applying indoxacarb to turf.  The short-term aggregate risk estimate for adults is below HED's level of concern.  The short- term aggregate assessment for children includes post-application exposure from indoor spray-treated surfaces.  The short-term aggregate risk estimate for children is below HED's level of concern.  Note that the indoor spray-treated aggregate assessment assumes only crack and crevice treatment since the spot-treated directed sprays exposure estimate was of concern by itself for children.

Table 7.2.1   Short-Term Aggregate Risk Calculations                  
                                  Population
                             Short- Term Scenario
                                       
                           LOC for Aggregate Risk[1]
                                    Dietary
                                    MOE[2] 
                       MOE Oral Residential Exposure[3] 
                    MOE Inhalation Residential Exposure[4]
                Aggregate MOE (food, water, and residential)[5]
                                    Adult 
                                      100
                                     1800
                                      NA
                                    13,000
                                     1600
                              Child (1<2 yrs)
                                      100
                                      840
                                      160
                                  6.2 x 10[7]
                                      130
[1] LOC=100 (10x inter- and 10x intra- species uncertainty factors)
[2] MOE dietary = [(short- -term oral NOAEL)/(chronic dietary exposure)].  Oral NOAEL= 2 mg/kg/day.  Chronic dietary exposure value from Table 5.4.5  
[3] MOE oral = [(short- -term oral NOAEL)/(hand-to-mouth residential exposure)].  Oral NOAEL= 2 mg/kg/day.  Oral exposure value from Table 6.3.2 (indoor use)  
[4]MOE inhalation = [(short-term oral NOAEL)/(inhalation exposure). Oral NOAEL= 2 mg/kg/day .Inhalation exposure value from Table 6.3.2 (turf or indoor use)
[5]MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE inhalation)]

7.3	Intermediate-/Long-Term (Chronic) Aggregate Risk

The intermediate-/long-term (or chronic) aggregate risk for indoxacarb includes contribution from dietary (food and drinking water) exposure plus the intermediate-/long-term post-application exposure to treated pets.  The intermediate-/long-term aggregate risk estimate for children post-application exposure to treated pets is below HED's level of concern (Table 7.3).  For adults, since there is no expectation of inhalation or non-dietary oral exposures to treated pets, the intermediate-/long-term aggregate risk assessment for indoxacarb is equivalent to chronic dietary risk assessment conducted in Section 5.4 of this document and is below HED's level of concern.

Table 7.3  Intermediate-/Long- Term Aggregate Risk Calculations 
                 Post-Application Treated Pets (KN128 )

Population
Long-Term Scenario

LOC for Aggregate Risk[1]
Dietary
MOE[2] 
MOE Oral Residential Exposure[3] 
MOE Inhalation Residential Exposure[4]
Aggregate MOE (food, water, and residential)[5]
Child (1<2 yrs)
                                      100
                                      840
                                      830
                                      NA
                                      420
[1] LOC=100 (10x inter- and 10x intra- species uncertainty factors)
[2] MOE dietary = [(long-term oral NOAEL)/(chronic dietary exposure)].  Oral NOAEL= 2 mg/kg/day.  Chronic dietary exposure value from Table 5.4.5  
[3] MOE oral = [(long-term oral NOAEL)/(hand-to-mouth residential exposure)].  Oral NOAEL= 2 mg/kg/day.  Residential exposure value from Table 6.3.1  
[4] Not applicable. Inhalation exposures not expected.
[5]MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE inhalation)]

7.4	Cancer Aggregate Risk

Indoxacarb is classified as "Not Likely to be Carcinogenic to Humans;" therefore, cancer risk is not a concern and cancer risks are not quantified.
8.0    Cumulative Exposure/Risk Characterization

EPA does not have, at this time, available data to determine whether indoxacarb, an oxadiazine class insecticide, has a common mechanism of toxicity with other substances.  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to indoxacarb and any other substances and indoxacarb does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that indoxacarb has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.
9.0    Occupational Exposure/Risk Characterization

The insecticide indoxacarb is formulated as granular, impregnated materials, water dispersible granules, emulsifiable, flowable, soluble concentrates, and solution-ready-to-use. Indoxacarb formulations can be used by homeowners and by commercial applicators to be used in agricultural and non-agricultural use sites 

IR-4 has proposed a Section 3 registration (Petition# 2E8029) for proposed foliar uses of the active ingredient indoxacarb on the following agricultural crops: 1) new uses on dry beans and succulent beans and  2) expanded crop group uses on small fruit vine climbing subgroup 13-07F and low-growing berry subgroup 13-07H. Occupational assessments are performed for the new uses on dry beans and succulent beans.  Existing grape and cranberry uses were reassessed in this document to reflect updates to the Agricultural Reentry Task Force (ARTF) database regarding transfer coefficients (TC) data since both crops are included in the new subgroups. The end-use products included in this IR-4 petition are Avaunt(R) 30% WDG (EPA Reg. No. 352-597) and Steward(TM) EC (EPA Reg. No. 352-638). 

The Avaunt[(R)] formulation contains an isometric mixture of 75% indoxacarb (insecticidally active S-enantiomer; DPX-KN128) and 25% of the R-enantiomer (insecticidally inactive; IN-KN127).  The percentage of active ingredient indicated on the Avaunt(R) label and the labeled use rates for each crop are based only on the amount of S-indoxacarb (KN128) and do not reflect the amount of the toxicologically significant R- enantiomer  (KN127).  Therefore, to determine combined exposures to both for risk assessment the maximum proposed label rate of application is adjusted to account for the 25% isomer not reflected on the label (i.e., lb total indoxacarb applied = application rate * 4/3).  The Steward product contains only the S-enantiomer (KN128); therefore, the proposed label rate does not need to be adjusted.

Avaunt[(R)] insecticide, a WDG formulation containing 30% of insecticidally active ingredient (S-indoxacarb) is proposed for foliar uses on dry beans, succulent beans, small fruit vine climbing subgroup 13-07F, and low-growing berry subgroup 13-07H at a maximum single application rate of 0.11 lb ai/acre or 0.147 lb total (S- and R-)  indoxacarb per acre (0.11 *4/3= 0.147). In addition, Steward[(R)] EC insecticide, an emulsifiable concentrate containing 15.84% of  S -indoxacarb (and no R-indoxacarb) is proposed for uses on dry beans at a maximum single application rate of 0.11 lb ai/acre.  

The proposed maximum seasonal application rate for dry and succulent beans and the low-growing berry subgroup is 0.44 lb ai/acre (4 applications at 0.11 lb ai/acre are permitted).  For the small fruit vine climbing subgroup, the proposed maximum seasonal application rate is of 0.22 lb ai./acre (2 applications at 0.11 lb ai/acre are permitted).  Aerial, airblast, ground foliar spray applications, and chemigation techniques (cranberry only) are the proposed application methods.  According to the proposed label, pre-harvest intervals (PHIs) range from 3 to 30 days.  The REI specified on the labels is 12 hours.  The proposed labels require applicators and other handlers to wear a long-sleeved shirt and long pants and shoes plus socks, plus chemical-resistant gloves.  The proposed uses and application rates are further described in Table 9.0.   
Table 9.0   Summary of Directions for Use of Indoxacarb.
Applic. Timing, Type, and  Equip.
Formulation [EPA Reg. No.]
Applic. Rate (lb ai/A) *
Max. No. Applic. per Season
Max. Seasonal Applic. Rate (lb ai/A)
PHI (days)
Use Directions and Limitations
                                 Beans, Dried 
                         Broadcast foliar applications
                           Air, Ground (groundboom)
                            DuPont (TM) Steward(R) EC
                                 15.84% ai EC
                            (EPA Reg. No. 352-638)
                                     0.11 
                                      NS
                                     0.44
                                       7
Retreatment interval (RTI) is 7 days
                         Broadcast foliar applications
                           Air, Ground (groundboom) 
                             DuPont (TM) Avaunt[(R)]
                                  30% ai WDG
                            (EPA Reg. No. 352-597)
                           0.11 (adjusted to 0.147)
                                      NS
                                     0.44
                              (adjusted to 0.586)
                                       7
Retreatment interval (RTI) is 7 days
                               Beans, Succulent
                         Broadcast foliar applications
                           Air, Ground (groundboom)
                             DuPont (TM) Avaunt[(R)]
                                  30% ai WDG
                            (EPA Reg. No. 352-597)
                           0.11 (adjusted to 0.147)
                                      NS
                                     0.44
                              (adjusted to 0.586)
                                       3
Retreatment interval (RTI) is 7 days
                   Small Fruit Vine Climbing Subgroup 13-07F
                         Broadcast foliar applications
                      Air, Ground (groundboom, airblast)
                             DuPont (TM) Avaunt[(R)]
                                  30% ai WDG
                            (EPA Reg. No. 352-597)
                           0.11 (adjusted to 0.147)
                                      NS
                                     0.22
                              (adjusted to 0.293)
                                       7
Retreatment interval (RTI) is 21 days
                       Low-Growing Berry Subgroup 13-07H
                         Broadcast foliar applications
            Air, Ground (groundboom), Chemigation (cranberry only),
                        Mechanically pressured hand-gun
                             DuPont (TM) Avaunt[(R)]
                                  30% ai WDG
                            (EPA Reg. No. 352-597)
                           0.11 (adjusted to 0.147)
                                      NS
                                 0.22 to 0.44
                      (0.293 to 0.586 depending on pest)
                                      30
Broadcast applications may need supplemental spot treatment in localized areas of heavy insect pressure
* Based on proposed application rates for DuPont (TM) Steward(R) EC (EPA Reg. No. 352-638) and DuPont (TM) Avaunt[(R)] (EPA Reg. No. 352-597) . DuPont (TM) Avaunt[(R)] contains an isometric mixture of 75% indoxacarb (insecticidally active S-enantiomer; DPX-KN128) and 25% of the R-enantiomer (insecticidally inactive; IN-KN127).  The percentage of active ingredient indicated on the Avaunt(R) label and the labeled use rates for each crop are based only on the amount of indoxacarb (KN128). Therefore, the maximum proposed label rate of application must be adjusted to account for the 25 % isomer not reflected as "ai" (i.e., lb total indoxacarb = application rate * 4/3).

9.1	Short- and Intermediate- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.  

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler inhalation (short-term and intermediate- term) exposure is expected from the proposed uses of indoxacarb on dry beans, succulent beans and the uses on small fruit vine climbing subgroup 13-07F and low-growing berry subgroup 13-07H .  Dermal exposure to handlers is not quantitatively assessed as a toxic endpoint is not identified for dermal exposure to indoxacarb. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: 

1) Mixing/loading liquids for aerial and groundboom applications;
2) Mixing/loading water dispersible granules for aerial, chemigation, airblast, and groundboom applications,
3) Applying Sprays via aerial equipment, airblast and groundboom equipment;
4) Mixing/loading/applying water dispersible granules via mechanically pressurized handgun;and, 
5) Flagging for aerial spray applications.

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table", which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website. 

Estimates of inhalation exposure were calculated at "baseline" level of personal protective equipment (PPE).  "Baseline" is defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. The proposed labels require applicators and other handlers to wear a long-sleeved shirt and long pants and shoes plus socks, plus chemical-resistant gloves.

A series of assumptions and exposure factors served as the basis for completing the occupational risk assessments.  See D411342, 5/1/13, complete details regarding body weight assumptions, absorption, unit exposures, area treated, exposure durations, and the associated calculations.

Summary of Occupational Handler Short-Term and Intermediate-Term  (Non-Cancer) Exposure and Risk Estimates
	
The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from the mid 1990's. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990's to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits.  The only data available is for exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, and socks); per the Agency's Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application.  With this level of protection, there are no risk estimates of concern for applicators.

Table 9.1 presents a summary of the short- and intermediate -term occupational handler exposures and risks. All occupational handler scenarios assessed result in inhalation MOEs that do not exceed HED's level of concern (MOEs >= 100) for short and intermediate-term exposure durations at label specified PPE (i.e ., no respirator ). 




Table 9.1  Occupational Handler ST and IT (Non-Cancer) Exposure and Risk Estimates for Indoxacarb.
                               Exposure Scenario
                                Crop or Target
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                                   (lb ai/A)
                Area Treated or Amount Handled Daily (acres)[3]
                                  Inhalation
                                       
                                       
                               Mitigation Level
                           (Baseline, no respirator)
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                 Mixer/Loader
Mixing/Loading Water Dispersible granules (WDG) for Aerial Applications
                Fruit, small vine climbing- Sub-group 13-07F  
                                     8.96
                                     0.147
                                      350
                                    0.00576
                                     1000

                                 Bean (snap), 
                                       
                                       
                                       
                                       
                                       

                          Low-Growing Berry Subgroup
                                    13-07H
                                       
                                       
                                       
                                       
                                       
Mixing/Loading Water Dispersible granules (WDG) for Aerial Applications
                                  Bean (dry)
                                     8.96
                                     0.147
                                     1,200
                                    0.0198
                                      300
Mixing/Loading Water Dispersible granules (WDG) for Airblast Applications
                 Fruit, small vine climbing- Sub-group 13-07F
                                     8.96
                                     0.147
                                      40
                                    0.00065
                                     9,000
Mixing/Loading Water Dispersible granules (WDG) for Chemigation Applications
                 Fruit, small vine climbing- Sub-group 13-07F
                                  (cranberry0
                                     8.96
                                     0.147
                                      350
                                    0.00576
                                     1,000
Mixing/Loading Water Dispersible granules (WDG) for Groundboom Applications
                                 Bean (snap),
                                     8.96
                                     0.147
                                      80
                                    0.00131
                                     4,600

                          Low-Growing Berry Subgroup
                                    13-07H
                                       
                                       
                                       
                                       
                                       
Mixing/Loading Water Dispersible granules (WDG) for Groundboom Applications
                                  Bean (dry)
                                  Bean (dry)
                                     8.96
                                     0.147
                                      200
                                    0.00329
                                     1,800
Mixing/Loading Liquid Flowables for Aerial Applications
                                       
                                     0.219
                                     0.11
                                     1,200
                                    0.0003
                                    16,000
Mixing/Loading Liquid Flowables for Groundboom Applications
                                       
                                     0.219
                                     0.11
                                      200
                                    0.00006
                                    98,000
                                  Applicator
Applying Sprays via Airblast Equipment (Open Cab)
                Fruit, small vine climbing- Sub-group 13-07F  
                                     4.71
                                     0.147
                                      40
                                    0.00034
                                    17,300
Applying Sprays via Groundboom Equipment 
                                 Bean (snap),
                                     0.32
                                     0.147
                                      80
                                    0.00005
                                    120,000

                          Low-Growing Berry Subgroup
                                    13-07H
                                       
                                       
                                       
                                       
                                       
Applying Sprays via Groundboom Equipment
                                  Bean (dry)
                                     0.34
                                     0.147
                                      200
                                    0.00012
                                    48,000

                                       
                                       
                                     0.11
                                       
                                    0.00009
                                    64,000
                                    Flagger
Flagging for Aerial Spray Applications 

                    Bean (snap), Low-Growing Berry Subgroup
          13-07H, and Fruit, small vine climbing- Sub-group 13-07F,  
                                     0.35
                                     0.147
                                      350
                                       
                                    0.00022
                                    27,000
Flagging for aerial spray applications 
                                       
                                  Bean (dry)
                                     0.35
                                     0.147
                                       
                                    0.00016
                                    27,000

                                       
                                     0.35
                                     0.11
                                       
                                    0.0001
                                    36,000
                            Mixer/Loader/Applicator
Applying Water Dispersible Granules Via Mechanically Pressurized Handgun 
                                       
                 Fruit, small vine climbing- Sub-group 13-07F
                                      3.9
                                     0.147
                                 1000 gallons
                                    0.00716
                                      840

                                 Bean (snap),
                                       
                                       
                                       
                                       
                                       

                          Low-Growing Berry Subgroup
                                    13-07H
                                       
                                       
                                       
                                       
                                       
1.	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" September 2012]); Level of mitigation: Baseline, PPE, Eng. Controls.
2.	Based on registered or proposed labels: DuPont (TM) Avaunt[(R)] 30% ai WDG (EPA Reg. No. 352-597) and DuPont (TM) Steward(R) EC 15.84% ai EC (EPA Reg. No. 352-638). The application rate used to calculate MOEs for Avaunt applications has been adjusted by a 4/3 factor to account for 4 parts of total indoxacarb for every 3 parts of S-indoxacarb.
3.	Exposure Science Advisory Council Policy #9.1.
4.	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
5.	Inhalation MOE = Inhalation NOAEL (6 mg/kg/day) / Inhalation Dose (mg/kg/day).

Occupational Handler Cancer Exposure and Risk Equations

Cancer risk estimates are not provided for indoxacarb since it is classified as not likely carcinogenic to humans. 

9.2	Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

Dermal and inhalation exposures to indoxacarb may occur for post-application workers. A quantitative dermal assessment is not performed since a dermal toxicity endpoint is not identified for indoxacarb. A quantitative occupational post-application inhalation exposure assessment was not performed for indoxacarb; however, an inhalation exposure assessment was performed for occupational/commercial handlers, which is likely to result in higher exposure than would occur post-application.  Therefore,  these handler inhalation exposure estimates would be protective of occupational post-application inhalation exposure scenarios.

9.2.1	Dermal Post-Application Risk

Occupational Post-Application Dermal Exposure Data and Assumptions
Short- and intermediate-term dermal post-application risk estimates were not quantified, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity to indoxacarb is not expected.   

Restricted Entry Interval

The REI specified on the proposed label is 12 hours and is based on the acute toxicity of Indoxacarb. Indoxacarb is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential.  It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to indoxacarb.
    
9.2.2	Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for indoxacarb at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), and low vapor pressure (2.5 x 10[-8]).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for indoxacarb.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.
10.0	References

A.Rivera-Lupianez, 5/1/13, D411342, Indoxacarb: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Bean (dry), Bean (snap), Bean (forage), and Small Fruit Vine Climbing Subgroup 13-07F and Low-Growing Berry Subgroup 13-07H. 

I. Negrón-Encarnación, 5/1/13, D408983, Indoxacarb Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13-07F and Low Growing Berry Subgroup (except strawberry) 13-07H. 

I. Negrón-Encarnación, 5/2/13, D408982, Indoxacarb.  Petition for the Establishment of Permanent Tolerances and Registration for Use on Dry Bean, Snap Bean, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13-07F and Low Growing Berry Subgroup (except strawberry) 13-07H.  Summary of Analytical Chemistry and Residue Data.

C. Koper, 11/06/12, D402100, Tier II Drinking Water Assessment for the New Use Registration of Indoxacarb on Dry Beans, Snap Beans, Small Fruit Vine Climbing Subgroup 13-07F and Low-Growing Berry Subgroup 13-07H.

D. Drew, 5/26/09, D365306, Indoxacarb.  Addendum to the Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13-07B and Beets (Garden).   

D. Drew, 5/18/09, D351087, Indoxacarb.  Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13-07B and Beets (Garden).  

HIARC Report on Indoxacarb,  HED Doc No. 013528 (June 24, 1999)







Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for indoxacarb are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.


Table A.1     Toxicology Requirements for Indoxacarb  

Guideline Number and Toxicity Study

                                   Required

                                   Satisfied

870.1100	Acute Oral Toxicity	
870.1200	Acute Dermal Toxicity	
870.1300	Acute Inhalation Toxicity	
870.2400	Primary Eye Irritation	
870.2500	Primary Dermal Irritation	
870.2600	Dermal Sensitization	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.3100	Oral Sub-chronic (Rodent)	
870.3150	Oral Sub-chronic (Non-Rodent)	
870.3200	21-Day Dermal	
870.3250	90-Day Dermal	
870.3465	90/28-Day Inhalation	

                                      yes
                                      yes
                                      yes
                                      CR
                                      CR

                                      yes
                                      yes
                                      yes
                                      --
                                      yes

870.3700	Developmental Toxicity  (Rodent)	
870.3700	Developmental Toxicity (Non-rodent)	
870.3800	Reproduction	

                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes

870.4100	Chronic Toxicity (Rodent)	
870.4100	Chronic Toxicity (Non-rodent)	
870.4200	Oncogenicity (Rat)	
870.4200	Oncogenicity (Mouse)	
870.4300	Chronic/Oncogenicity	

                                      yes
                                      no
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.5100	Mutagenicity: Gene Mutation - bacterial	
870.5300	Mutagenicity: Gene Mutation - mammalian	
870.5375	Mutagenicity: Structural Chromosomal Aberrations	
870.5395	Mutagenicity: Cytogenetics
870.5500	Mutagenicity: Other Genotoxic Effects	

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

870.6100	Acute Delayed Neurotoxicity (Hen)	
870.6100	90-Day Neurotoxicity (Hen)	
870.6200	Acute Neurotoxicity Screening Battery (Rat)	
870.6200	90-Day Neurotoxicity. Screening Battery (Rat)	
870.6300	Developmental Neurotoxicity	

                                      no
                                      no
                                      yes
                                      yes
                                      CR

                                       -
                                       -
                                      yes
                                      yes
                                      yes

870.7485	General Metabolism	
870.7600	Dermal Penetration	
870.7800     Immunotoxicity.......................................................................

                                      yes
                                      no
                                      yes

                                      yes
                                      yes
                                      yes


A.2	Toxicity Profiles


Table A.2.1   Acute Toxicity Data on Indoxacarb (DPX-KN128)
Guideline No./Study Type
MRID #
Results
Toxicity Category
870.1100 Acute oral toxicity
44477115
LD50 = 179 (F) and 843 (M) mg/kg (rat)
II
870.1200 Acute dermal toxicity
46240001
LD50 > 5000 mg/kg (rat)
IV
870.1300 Acute inhalation toxicity
N/A
N/A
IV
870.2400 Primary eye irritation
46240002
Not a eye irritant (rabbit)
IV
870.2500 Primary dermal irritant
46240003
Not a dermal irritant (rabbit)
IV
870.2600 Skin sensitization
46240004
Is a dermal sensitizer (Guinea Pig)
NA

Table A.2.2 Acute Toxicity Data on DPX-MP062 Technical (94.5%;)
                                               80% DPX KN128,  20% IN KN127

Study
Type
MRID #
                                    Results
                               Toxicity Category
870.1100 Acute oral toxicity

44477113

LD50 = 	
1730mg/kg males
268 mg/kg females
<1000 mg/kg combined (rat)
      II
870.1200 Acute dermal toxicity

44477118
LD50 >5000mg/kg (limit test) (rat)
                                      IV
870.1300 Acute inhalation toxicity

70%MUP
 44477120
LC50 > 5.5 mg/L males, females and combined
                                      IV
870.2400 Primary eye irritation

44477122
Moderate eye irritant (rabbit)
                                      III
870.2500 Primary dermal irritant
44477125
Not a dermal irritant (rabbit)
                                      IV
870.2600 Skin sensitization
44477126
Magnusson-Kligman Maximization test, Is a dermal sensitizer (Guinea Pig)
                                      NA

Table A.2.3   Acute Toxicity Data on DPX-JW062 (50% DPX KN128,50% IN KN127)

Guideline No./ Study Type

MRID No.

                                    Results

                               Toxicity Category

870.1100 Acute oral toxicity

44701601
                                       

LD50 > 5000 mg/kg (males, females, combined) (in corn oil)

IV

870.1200 Acute dermal toxicity

44477119

LD50 > 2000 mg/kg (males, females, combined) (rabbit)

III

870.1300 Acute inhalation toxicity

44477121

LC50 > 5.4 mg/L males
LC50 = 4.2 mg/L females (rat)

IV

870.2400 Primary eye irritation

44701602

Slight eye irritant (rabbit)

IV

870.2500 Primary dermal irritation

44701603

Slight dermal irritation (rabbit)

IV

870.2600 Skin sensitization

44701604

Is not a dermal sensitizer Magnusson-Kligman Maximization test, (Guinea Pig)

NA

Table A.2.4   Sub-Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX-KN128)

                           Guideline No./ Study Type

                    MRID No. (year)/ Classification /Doses

870.3700a
Prenatal developmental in rodents - rat
46240005(2004)
Acceptable/guideline
0, 0.5, 1.0, 2.0, or 3.5 mg/kg/day
Maternal NOAEL = 2.0 mg/kg/day
LOAEL = 3.5 mg/kg/day, based on decrease in maternal overall body-weight gain and adjusted body-weight gain.
Developmental NOAEL = 2.0 mg/kg/day
LOAEL = 3.5 mg/kg/day, based on decreased mean fetal weight.

Gene Mutation
870.5100

46240006 (2004) Acceptable/guideline


strains TA98, TA100, TA1535 and TA1537 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 2.5-5000 μg/plate


Gene Mutation
870.5300
46240007 (2003)
Acceptable/guideline

negative for mutagenic activity for the following concentration range 5-50 μg/mL (+-S9)


Cytogenetics 
870.5375
46240008 (2003)
Acceptable/guideline
no evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 1.25-100 μg/mL (+S9)

870.6300
Developmental neurotoxicity - rat

46749002 (2006)
46749003 (2006)
Acceptable/non-guideline
0, 0.5, 1.0, 1.5, or 3.0 mg/kg/day
Maternal systemic/neurotoxicity NOAEL = 1.5 mg/kg/day
LOAEL = 3.0 mg/kg/day, based on the adverse clinical signs observed, decreased body-weight gain and food consumption and mortality.
Offspring systemic/neurotoxicity NOAEL= 1.5 mg/kg/day
LOAEL = 3.0 mg/kg/day, based on an increased incidence of stillbirths, decreased mean pup body weight at birth and increased pup mortality during PND 1-4 in males and females, and increase in number of learning trials to reach criterion and increased latency in males.
870.7800
Immunotoxicity
48478002 (2011)
Acceptable/guideline

Immunotoxicity NOAEL=23 mg/kg/day HDT 
Systemic NOAEL=23 mg/kg/day HDT
Systemic LOAEL was not established (>23 mg/kg/day).





Table A.2.5     Sub-Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX-MP062)
                         80% DPX KN128,  20% IN KN127

                           Guideline No./ Study Type

                    MRID No. (year)/ Classification /Doses

                                    Results

870.3100
90-Day oral toxicity rodents

44477129 (1997)
Acceptable/guideline
M: 0, 10, 50, 100, 200 ppm
M: 0, 0.6, 3.1, 6.0, 15 mg/kg/day
F: 0, 10, 25, 50, 100 ppm, F: 0, 0.76, 2.1, 3.8, 8.9 mg/kg/day

NOAEL =  3.1 (M), 2.1 (F) mg/kg/day
LOAEL =  6.0 (M), 3.8 (F) mg/kg/day based on decreased body weight, body-weight gain, food consumption and food efficiency.


870.3200
28-Day dermal toxicity

44477134 (1997)
acceptable (guideline)
0, 50, 500, 1000, 2000 mg/kg/day

NOAEL = 2000 mg/kg/day
LOAEL = >2000 mg/kg/day in rats.

870.3200
28-Day dermal toxicity

44983901 (1999)
acceptable/guideline
0, 50, 500, 1000, 2000 mg/kg/day

NOAEL = 50 mg/kg/day
LOAEL = 500 mg/kg/day based on decreased body weights, body-weight gains, food consumption, and food efficiency in F, and changes in hematology parameters (incr. reticulocytes), the spleen (incr. abs. and rel. weight - M only, gross discoloration), clinical signs of toxicity in both sexes in rats.
[Based on the in vitro dermal absorption data from rat skin and human skin (i.e. 15.2% and 0.87%, respectively), the human equivalent NOAEL is 875 mg/kg/day (i.e. 50 x 15.2%/0.87%). Thus, the calculated human dermal LOAEL of 8750 mg/kg/day exceeds the dermal limit dose of 1000 mg/kg/day. See MRIDs 45911401, 45911402, 45911403]
870.3465
28-Day inhalation toxicity
45870001 (2003)
Acceptable/non-guideline
0, 4.6, 23, 290 ug/L/day
NOAEL = 23 ug/L/day
LOAEL = 290 ug/L/day (75.69 mg/kg/day), based on increased absolute and relative spleen weights, pigmentation and hematopoiesis in the spleen, and hematological changes.

870.3700a
Prenatal developmental in rodents - rat

44477138, 44477142 (1997)
Acceptable (guideline)
0.0, 0.5, 1.0, 2.0, or 4.0 mg/kg/day (in PEG)
Maternal NOAEL = 2.0 mg/kg/day
LOAEL = 4.0 mg/kg/day based on decreased mean body weights, body-weight gains, food consumption.
Developmental NOAEL = 2.0 mg/kg/day
LOAEL = 4.0 mg/kg/day based on decreased fetal weights.

Gene Mutation
870.5100

44477149 (1997)
acceptable/guideline


Negative: strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 10-5000 μg/plate

Gene Mutation
870.5300

44477147 (1997)
acceptable/guideline
Negative: negative for mutagenic activitity for the following concentration ranges: 3.1-250 μg/mL (-S9); 3.1-250 μg/mL (+S9)

Cytogenetics 
870.5375

44477146 (1996)
acceptable/guideline
Negative: no evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 15.7-1000 μg/mL (+S9)

Cytogenetics 
870.5395

44477148 (1997)
acceptable/guideline
Negative: no evidence of mutagenicity for the following dose ranges: 3000-4000 mg/kg - males; 1000-2000 mg/kg - females

Other Effects 
870.5550

44477151 (1997)
acceptable/guideline
Negative: no evidence of mutagenic activity at the following concentration range: 1.56-200 μg/mL; cytotoxicity was seen at concentrations of >100 μg/mL

870.6200a
Acute neurotoxicity screening battery

44477127 (1997)
acceptable/guideline
M: 0, 25, 100, 200 mg/kg
F: 0, 12.5, 50, 100 mg/kg
NOAEL =  100 mg/kg (M),  12.5 mg/kg (F)
LOAEL = 200 mg/kg (M) based on decreased body-weight gain, decreased food consumption, decreased forelimb grip strength, and decreased foot splay. 50 mg/kg (M) based on decreased body weight and body-weight gain

870.6200b
Subchronic neurotoxicity screening battery

44477135 (1997)
acceptable/guideline
M: 0, 10, 100, 200 ppm 0.57, 5.6, 12 mg/kg/d, F: 0, 10, 50, 100 ppm
0.68, 3.3, 6.1 mg/kg/d

NOAEL =0.57 (M),  0.68 (F) mg/kg/day
LOAEL =  5.6 (M),  3.3 (F) mg/kg/day based on decreased body weight and alopecia.


870.7600
Dermal penetration

(Triple pack study)
45911401 (2002) 45911402 (2002)
45911403 (2002)
Acceptable/guideline
0, 13.3, 2000 ug/cm2 for 6 hours

Dermal absorption ranged from 0.41% to 0.94% following 6 hours exposure in rats.  Following a 162 hours post dosing, the absorption in rats ranged from 0.88% to 4.91% depending upon the dose/dilution. 

The in vitro dermal absorption for rat skin was 15.2% and the in vitro dermal absorption in human skin was 0.87%, or 17.5X lower. The equivalent dermal absorption in humans was calculated to be 0.28%.


Table A.2.6  Sub-Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX-JW062)
(50% DPX KN128, 50% IN KN127)
                                       
Guideline No./ Study Type
                                       
MRID No. (year)/ Classification/Doses
                                       
                                    Results

870.3700a
Prenatal developmental in rodents - rat

44477140, 44477143 (1997)
acceptable/guideline
0, 10, 100, 500, 1000 mg/kg/day (in methyl cellulose)

Maternal NOAEL = 10 mg/kg/day
LOAEL = 100 mg/kg/day based on mortality, clinical signs, and decreased mean body weights, body-weight gains, and food consumption.
Developmental NOAEL = 10 mg/kg/day
LOAEL = 100 mg/kg/day based on decreased numbers of live fetuses/litter.

870.3700a
Prenatal developmental in rodents - rat

44477139 (1997)
acceptable/guideline
0, 20, 40, 80, or 120 ppm
1.11, 2.2, 4.1, 5.7 mg/kg/day (rounded to 2 sig. fig.)

Maternal NOAEL = 1.1 mg/kg/day
LOAEL = 2.2 mg/kg/day based on decreased mean body weights, body-weight gains, food consumption, and food efficiency.
Developmental NOAEL = 1.1 mg/kg/day
LOAEL = 4.1 mg/kg/day based on decreased fetal body weights.

870.3700b
Prenatal developmental in nonrodents - rabbit

44477141 (1995)
acceptable/guideline
0, 250, 500, or 1000 mg/kg/day in methyl cellulose

Maternal NOAEL = 500 mg/kg/day
LOAEL = 1000 mg/kg/day based on slight decreases in maternal body-weight gain and food consumption.
Developmental NOAEL = 500 mg/kg/day
LOAEL = 1000 mg/kg/day based on decreased fetal body-weights and reduced ossification of the sternebrae.

870.3800
Reproduction and fertility effects

44477144 (1997)
acceptable/guideline
0, 20, 60, 100 ppm
M: 0, 1.3, 3.9, 6.4 mg/kg/d
F: 0, 1.5, 4.4, 6.9 mg/kg/d

Parental/Systemic NOAEL = 1.5 mg/kg/day
LOAEL = 4.4 mg/kg/day based on decreased body weights, body-weight gains, and food consumption of F0 females, and incr. spleen weights in the F0 and F1 females.
Reproductive NOAEL = 6.4 mg/kg/day
LOAEL > 6.4 mg/kg/day.
Offspring NOAEL = 1.5 mg/kg/day
LOAEL = 4.4 mg/kg/day based on decrease in the body weights of the F1 pups during lactation.

870.4100a
Chronic toxicity rodents - rat

44477145 (1997)
acceptable/guideline
0, 20, 40, 60, 125, 250 ppm 
M: 0, 0.80, 1.6, 2.4, 5.0, 10 mg/kg/day
F: 0, 10, 20, 40, 60, 125 ppm 
0, 0.55, 1.0, 2.1, 3.6, 7.8 mg/kg/day

NOAEL =  5 (M),  2.1 (F) mg/kg/day
LOAEL = 10 (M),  3.6 (F) mg/kg/day based on decreased body weight, body-weight gain, and food consumption and food efficiency; decreased HCT, HGB and RBC at 6 months in F only.

No evidence of carcinogenic potential.

870.4100b
Chronic toxicity dogs

44477136 (1997)
acceptable/guideline
0, 40, 80, 640, 280 ppm
M: 0, 1.1, 2.3, 18, 34 mg/kg/day
F: 0, 1.3, 2.4, 19, 36 mg/kg/day

NOAEL =  2.3 (M),  2.4 (F) mg/kg/day
LOAEL =  18 (M),  19 (F) mg/kg/day based on decreased HCT, HGB and RBC; incr. Heinz bodies and reticulocytes and assoc. secondary microscopic changes in the liver, kidneys, spleen, and bone marrow; incr. abs. and rel. liver weights.


870.4200
Carcinogenicity rats

see 870.4100a

see 870.4100a
No evidence of carcinogenicity.

870.4300
Carcinogenicity mice

44477137 (1997)
0, 20, 100, 200/150/125 ppm
M: 2.6, 14, 22 mg/kg/day
F: 4.0, 20, 31 mg/kg/day
(rounded to 2 sig. fig.)

NOAEL =  2.6 (M), 4.0 (F) mg/kg/day
LOAEL =  14 (M),  20 (F) mg/kg/day based on decreased body weight, body-weight gain, and food efficiency and clinical signs indicative of neurotoxicity.
No evidence of carcinogenicity.

Gene Mutation
870.5100

44701606 (1995)
acceptable/guideline


Negative: strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 10-5000 μg/plate.

Gene Mutation
870.5300

44701607 (1995)
acceptable/guideline

Negative for mutagenic activity for the following concentration ranges:  Negative;100-1000 μg/mL (-S9); 100-1000 μg/mL (+S9), precipitate >1000 μg/mL

Cytogenetics 
870.5375

44701608 (1995)
acceptable/guideline
Negative: No evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 19-300 μg/mL (-S9), 19-150 μg/mL (+S9); partial insoluble & cytotoxicity > 150 μg/mL

Cytogenetics 
870.5395

44701610 (1995)
Negative: No evidence of mutagenicity at 2500 or 5000 mg/kg

Other Effects 
870.5550

44701609 (1995)
acceptable/guideline

Negative: No evidence of mutagenic activity at the following concentration range: 0.1-50 μg/mL, cytotoxicity observed at >50 μg/mL

870.6200a
Acute neurotoxicity screening battery

44477128 (1996)
acceptable/guideline
0, 500, 1000, 2000 mg/kg

      
NOAEL >=  2000 mg/kg (M)
      =  < 500 mg/kg (F)
LOAEL >  2000 mg/kg (M)
       < 500 mg/kg (F) based on clinical signs, decreased body-weight gains and food consumption, and FOB effects

870.7485
Metabolism and pharmacokinetic

44477152, 44477153 (1997)
acceptable/guideline


Both indoxacarb and JW062 were extensively meta - bo - lized and the metabolites were eliminated in urine, feces, and bile. The metabolite profile for JW062 was dose dependent and varied quantita - tive - ly between males and females. Differences in metabolite profiles were also observed for the different label positions (indanone and trifluoromethoxyphenyl rings). All biliary metabolites undergo further biotransformation in the gut. The proposed metabolic pathway for both indoxacarb and JW062 has multiple metabolites bearing one of the two ring structures.
Appendix B.  Physical/Chemical Properties

Table B.1	Physicochemical Properties of Indoxacarb
Parameter
Value
Reference
Melting point/range
140-141ºC
DP# D244253, S. Levy, 1/19/2000
pH
5.32 at 25ºC

Density
1.34 at 20ºC

Water solubility
15.4 +- 2.3 ppb in pH 5 buffer
800 ppb at pH 7 (20[◦]C)[1]

Solvent solubility
1.72 g/L in n-heptane; 14.5 g/L in 1-octanol; 103 g/L in methanol; 117 g/L in o-xylene; 139 g/L in acetonitrile; 160 g/L in ethyl acetate; and >250 g/kg in methylene chloride, acetone, and dimethyl-formamide

Vapor pressure (25°C)
2.5 x 10[-8] Pa (1.9x10[-10] mmHg)

Dissociation constant, pKa
Does not dissociate at pHs of 2.42-11.36

Octanol/water partition coefficient, Log(KOW)
4.65 at pH 5

UV/visible absorption spectrum
Molar absorptivities at three maxima were affected by pH, but not over wavelengths of environmental significance.

1 EFED memo D402100, 11/6/12



Appendix C.  Review of Human Research


This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.  

